1
00:00:05,353 --> 00:00:08,656
 THANKS VERY MUCH FOR THE

2
00:00:08,656 --> 00:00:09,057
 INVITATION.

3
00:00:09,057 --> 00:00:09,691
 FANTASTIC MEETING.

4
00:00:09,691 --> 00:00:11,426
 I AM ALREADY ENJOYING THE

5
00:00:11,426 --> 00:00:13,194
 FIRST DAY AND LOOKING FORWARD

6
00:00:13,194 --> 00:00:13,595
 TO THE DAY.

7
00:00:13,595 --> 00:00:18,666
 IT IS ALSO A PLEASURE TO BE 

8
00:00:18,666 --> 00:00:20,835
 BACK IN BETHESDA, GREAT

9
00:00:20,835 --> 00:00:22,670
 SCIENCE, GREAT DISCUSSIONS,

10
00:00:22,670 --> 00:00:23,571
 GREAT FRIENDSHIP SO THANKS

11
00:00:23,571 --> 00:00:25,540
 AGAIN FOR GIVING ME THIS

12
00:00:25,540 --> 00:00:26,407
 OPPORTUNITY TO COME AND VISIT

13
00:00:26,407 --> 00:00:28,476
 AND I AM HAPPY TO SHARE WITH

14
00:00:28,476 --> 00:00:30,211
 YOU WHAT WE HAVE BEEN DOING IN

15
00:00:30,211 --> 00:00:34,082
 THE FIELD OF INNATE LYMPHOID

16
00:00:34,082 --> 00:00:34,382
 CELLS.

17
00:00:34,382 --> 00:00:36,985
 I THINK EVERYBODY IN THE

18
00:00:36,985 --> 00:00:39,754
 AUDIENCE KNOWS ABOUT LYMPHOID

19
00:00:39,754 --> 00:00:40,889
 CELLS, PROBABLY HEARD ABOUT

20
00:00:40,889 --> 00:00:43,558
 THEM SO HOW DO WE FRAME THESE

21
00:00:43,558 --> 00:00:49,063
 CELLS IN THE CONTEXT OF

22
00:00:49,063 --> 00:00:55,603
 ILLNESS AND THEY ARE THE --

23
00:00:55,603 --> 00:00:59,240
 SIMILAR TO THE T CELLS WE ALSO

24
00:00:59,240 --> 00:01:00,141
 KNOW.

25
00:01:00,141 --> 00:01:06,681
 WE HAVE PARALLELS BETWEEN 

26
00:01:06,681 --> 00:01:17,158
 THESE DIFFERENT HEALTH 

27
00:01:20,395 --> 00:01:30,505
 PARIASES, T1, T2, T3 AND SO WE

28
00:01:30,505 --> 00:01:32,507
 HAVE ASKED ABOUT THEM, WHY WE

29
00:01:32,507 --> 00:01:38,713
 HAVE THESE CELLS THAT ARE MORE

30
00:01:38,713 --> 00:01:39,547
 ANTIGENT AND OTHERS ARE MORE

31
00:01:39,547 --> 00:01:41,683
 OPEN IN THE WAY THEY CAN

32
00:01:41,683 --> 00:01:45,053
 REACT, WHO DOES WHAT, WHEN AND

33
00:01:45,053 --> 00:01:49,157
 WHERE AND ALSO SOME

34
00:01:49,157 --> 00:01:50,725
 PHILOSOPHICAL QUESTIONS AS

35
00:01:50,725 --> 00:01:54,562
 WELL WITH THE T CELLS AND

36
00:01:54,562 --> 00:01:55,597
 DETERMINING FACTORS WITH

37
00:01:55,597 --> 00:01:59,033
 SULPHATE AND NOW WE HAVE T

38
00:01:59,033 --> 00:02:00,802
 CELLS THAT DON'T REACT.

39
00:02:00,802 --> 00:02:02,303
 SO A LOT OF QUESTIONS.

40
00:02:02,303 --> 00:02:05,139
 WE HAVE LEARNED HOW THEY REACT

41
00:02:05,139 --> 00:02:06,941
 TO INFECTION, AN INSTANT WAY

42
00:02:06,941 --> 00:02:13,615
 TO START THINKING ABOUT THEM 

43
00:02:13,615 --> 00:02:15,950
 ESPECIALLY IN T CELL HEALTH

44
00:02:15,950 --> 00:02:20,154
 AND SO WE THINK OF THEM HOW

45
00:02:20,154 --> 00:02:24,392
 THEY FIT IN IN THE KIND OF

46
00:02:24,392 --> 00:02:26,361
 FASHION PEOPLE CAN GRAB ON TO

47
00:02:26,361 --> 00:02:28,763
 AND ACCEPT IN TERMS OF THE

48
00:02:28,763 --> 00:02:30,265
 INDICATE SKATERS OUTPUT OF THE

49
00:02:30,265 --> 00:02:31,532
 CELLS AND THEIR IMMUNE

50
00:02:31,532 --> 00:02:31,899
 RESPONSES.

51
00:02:31,899 --> 00:02:33,468
 BUT WHEN YOU LOOK A LITTLE

52
00:02:33,468 --> 00:02:34,869
 DEEPER, YOU SEE THERE ARE SOME

53
00:02:34,869 --> 00:02:37,238
 ASPECTS OF THE BIOLOGY OF THE

54
00:02:37,238 --> 00:02:39,974
 CELLS WHICH ASK NOT

55
00:02:39,974 --> 00:02:41,542
 NECESSARILY -- DOES NOT

56
00:02:41,542 --> 00:02:43,011
 NECESSARILY MATCH WITH

57
00:02:43,011 --> 00:02:43,378
 INFECTION.

58
00:02:43,378 --> 00:02:46,547
 YOU HAVE SOME THAT ARE RELATED

59
00:02:46,547 --> 00:02:47,715
 TO THE HOMEOSTASIS AT THE

60
00:02:47,715 --> 00:02:49,684
 TISSUE LEVEL AND THERE MAY BE

61
00:02:49,684 --> 00:02:51,119
 FUNCTIONS JUST BEYOND HAVING

62
00:02:51,119 --> 00:02:54,022
 ANOTHER SET OF CELLS IMPORTANT

63
00:02:54,022 --> 00:02:55,757
 IN DEFENDING US AGAINST

64
00:02:55,757 --> 00:02:57,625
 DIFFERENT TYPES OF PATHOGENS.

65
00:02:57,625 --> 00:02:58,993
 AND THAT HAS COME TO BE TRUE

66
00:02:58,993 --> 00:03:00,962
 AND WE HAVE LEARNED A LOT

67
00:03:00,962 --> 00:03:11,439
 ABOUT HOW NOW ILCS ARE 

68
00:03:16,177 --> 00:03:17,979
 INVOLVED IN ACTIVITIES ON THE

69
00:03:17,979 --> 00:03:24,619
 LEVEL THAT ARE NOT RELATED TO

70
00:03:24,619 --> 00:03:25,687
 THOSE FUNCTIONS AND WE HAVE

71
00:03:25,687 --> 00:03:28,089
 LEARNED HOW THE CELLS MAY BE

72
00:03:28,089 --> 00:03:29,691
 INVOLVED IN OPERATING AT THE

73
00:03:29,691 --> 00:03:30,925
 SYSTEMIC LEVEL.

74
00:03:30,925 --> 00:03:33,027
 TISSUE REPAIR IS ANOTHER AREA

75
00:03:33,027 --> 00:03:34,395
 THAT IS EXTREMELY INTERESTING

76
00:03:34,395 --> 00:03:39,267
 AND A LOT OF PURCHASE --

77
00:03:39,267 --> 00:03:40,802
 PURSUAL IN THIS AREA, TRYING

78
00:03:40,802 --> 00:03:42,837
 TO UNDERSTAND HOW THEY ARE

79
00:03:42,837 --> 00:03:46,507
 IMPORTANT FOR TISSUE REPAIR

80
00:03:46,507 --> 00:03:48,276
 AND REGENERATION FOLLOWING

81
00:03:48,276 --> 00:03:50,244
 INJURY AND THEN WE LEARNED

82
00:03:50,244 --> 00:03:52,380
 ABOUT HOW THEY OPERATE WITH

83
00:03:52,380 --> 00:03:53,848
 THE NERVOUS SYSTEM, DAVID WILL

84
00:03:53,848 --> 00:03:57,785
 HAVE THINGS TO SAY WITH --

85
00:03:57,785 --> 00:04:00,588
 ABOUT THAT HERE AND THERE HAVE

86
00:04:00,588 --> 00:04:05,326
 BEEN A NUMBER OF WAYS THAT THE

87
00:04:05,326 --> 00:04:06,361
 I OC ACTIVATION ARE TAKING

88
00:04:06,361 --> 00:04:07,795
 PLACE AND I THINK WE'RE AT THE

89
00:04:07,795 --> 00:04:09,464
 TIP OF THE ICEBERG WITH HOW

90
00:04:09,464 --> 00:04:10,898
 THE CELLS ARE WORKING.

91
00:04:10,898 --> 00:04:13,568
 SO WE WERE INTERESTED FROM A

92
00:04:13,568 --> 00:04:14,435
 DEVELOPMENTAL STANDPOINT TO

93
00:04:14,435 --> 00:04:15,903
 TRY TO UNDERSTAND HOW THE

94
00:04:15,903 --> 00:04:17,505
 CELLS ARE MADE AND WE LEARNED

95
00:04:17,505 --> 00:04:19,807
 A LOT FROM OTHER GROUPS AND

96
00:04:19,807 --> 00:04:26,013
 ESPECIALLY A NUMBER OF 

97
00:04:26,013 --> 00:04:31,552
 IMPORTANT CONTRIBUTIONS BY

98
00:04:31,552 --> 00:04:32,920
 ALBERT VILLAGE DELAC AND

99
00:04:32,920 --> 00:04:35,656
 SEVERAL IN THE AUDIENCE OF THE

100
00:04:35,656 --> 00:04:39,494
 PREOCCURS SORES ABLE TO GIVE

101
00:04:39,494 --> 00:04:41,229
 RISE TO ILCS AND THOSE CELLS

102
00:04:41,229 --> 00:04:42,897
 ARE VERY IMPORTANT BECAUSE

103
00:04:42,897 --> 00:04:45,266
 THEY ALLOW US TO MAP THE

104
00:04:45,266 --> 00:04:47,535
 DEVELOPMENTAL PATHWAY AND OF

105
00:04:47,535 --> 00:04:48,903
 COURSE MANY OTHER GROUPS

106
00:04:48,903 --> 00:04:51,439
 CONTRIBUTED TO THIS BY LOOKING

107
00:04:51,439 --> 00:04:54,675
 AT INDIVIDUAL TRANSCRIPT

108
00:04:54,675 --> 00:04:58,946
 SCRIPTION FACTORS AND ALLOWS 

109
00:04:58,946 --> 00:05:06,988
 US TO LOOK AT OTHER THINGS AND

110
00:05:06,988 --> 00:05:08,890
 WE HAVE THIS MAP.

111
00:05:08,890 --> 00:05:10,992
 SO WE WERE INTERESTED IN

112
00:05:10,992 --> 00:05:18,933
 REPORTER MICE AND LOOKED AT 

113
00:05:18,933 --> 00:05:23,371
 THE WORK OF ILC2 THAT GAVE US

114
00:05:23,371 --> 00:05:26,407
 SOME REHAB BILL TORE PATHWAYS

115
00:05:26,407 --> 00:05:28,209
 AND SOME PEOPLE WORKING IN

116
00:05:28,209 --> 00:05:31,913
 THIS AREA ABOUT HOW NK CELLS

117
00:05:31,913 --> 00:05:38,553
 AND ILCS MAY BE INDEPENDENTLY

118
00:05:38,553 --> 00:05:44,525
 WORKING OR ARE RELATED AND 

119
00:05:44,525 --> 00:05:48,496
 SHOWN HERE, POSTDOC WITH

120
00:05:48,496 --> 00:05:51,432
 AYING, MANY OF YOU KNOW HER,

121
00:05:51,432 --> 00:05:53,100
 AND SHE HOOKED UP WITH AN

122
00:05:53,100 --> 00:05:55,436
 INDIVIDUAL WHO HAS MADE A

123
00:05:55,436 --> 00:05:56,904
 CAREER OF GROWING T CELLS IN

124
00:05:56,904 --> 00:05:58,706
 CULTURE AND THEY SET UP

125
00:05:58,706 --> 00:06:01,476
 CONDITIONS TO GROW HUMAN ILCS

126
00:06:01,476 --> 00:06:03,511
 IN THE LABORATORY AND THAT LED

127
00:06:03,511 --> 00:06:04,812
 TO DISCOVERING THIS POPULATION

128
00:06:04,812 --> 00:06:07,915
 IN THE BLOOD WHICH ACTUALLY

129
00:06:07,915 --> 00:06:09,584
 HAS ILC PRECURSOR ACTIVITY.

130
00:06:09,584 --> 00:06:12,119
 SO HUMANS HAVE IN THEIR

131
00:06:12,119 --> 00:06:13,254
 CIRCULATION THE PREOCCURS

132
00:06:13,254 --> 00:06:15,790
 SORES FOR ALL THE DIFFERENT

133
00:06:15,790 --> 00:06:17,625
 ILCS AND IF YOU LOOK AT THE

134
00:06:17,625 --> 00:06:19,260
 ONES WE FOUND IN MICE AND

135
00:06:19,260 --> 00:06:22,930
 FOUND IN BLOOD YOU CAN SEE

136
00:06:22,930 --> 00:06:23,698
 TRANSCRIPTIONALLY THEY ARE

137
00:06:23,698 --> 00:06:29,537
 VERY CLOSE AND ABLE TO GIVE 

138
00:06:29,537 --> 00:06:34,342
 RISE IN VITRO AND IN VIVO TO

139
00:06:34,342 --> 00:06:35,109
 SOME ILK CELLS.

140
00:06:35,109 --> 00:06:37,578
 THEY ARE NOT COMMITTED TO ANY

141
00:06:37,578 --> 00:06:39,847
 FATE, THEY ARE MULTIPOTENT AND

142
00:06:39,847 --> 00:06:42,416
 THEIR SULPHATE IS DETERMINED

143
00:06:42,416 --> 00:06:43,084
 ENVIRONMENTALLY.

144
00:06:43,084 --> 00:06:44,886
 SO IT SETS UP AN INTERESTING

145
00:06:44,886 --> 00:06:45,853
 SCENARIO WHERE YOU HAVE THESE

146
00:06:45,853 --> 00:06:47,588
 CELLS AND YOU HAVE TO NOW

147
00:06:47,588 --> 00:06:49,056
 DISCOVER HOW THEY ARE GOING

148
00:06:49,056 --> 00:06:50,191
 ABOUT THEIR DIFFERENT

149
00:06:50,191 --> 00:06:50,791
 CONSIDERATION PROCESS.

150
00:06:50,791 --> 00:06:55,730
 SO WE HAVE AN ENTRY POINT IN

151
00:06:55,730 --> 00:06:57,865
 HUMANS, A VERY ENTRY POINT FOR

152
00:06:57,865 --> 00:06:59,800
 DISEASE ARE IN THE BLOOD.

153
00:06:59,800 --> 00:07:01,836
 HAVING THEM IN CIRCUMSTANCE

154
00:07:01,836 --> 00:07:03,371
 CIRCULATION LED US TO PROPOSE

155
00:07:03,371 --> 00:07:08,843
 HOW THEY MIGHT DEVELOP, THIS

156
00:07:08,843 --> 00:07:11,279
 IS ILC SITUATION IN SITU AND

157
00:07:11,279 --> 00:07:13,881
 WHAT IS HAPPENING IS THEY ARE

158
00:07:13,881 --> 00:07:16,317
 ABLE TO ENTER THE BODY

159
00:07:16,317 --> 00:07:17,418
 ANYWHERE WHERE THEY CAN

160
00:07:17,418 --> 00:07:20,421
 RECEIVE THE NECESSARY SIGNALS

161
00:07:20,421 --> 00:07:21,989
 THAT HAVE EFFECTIVE FUNCTION

162
00:07:21,989 --> 00:07:23,257
 RELATIVE TO THAT TISSUE.

163
00:07:23,257 --> 00:07:26,827
 SO IT IS A MATTER OF MAKING

164
00:07:26,827 --> 00:07:28,262
 ILCS ON DEMAND AND IN THE

165
00:07:28,262 --> 00:07:29,630
 RIGHT PLACE AND THE RIGHT

166
00:07:29,630 --> 00:07:30,197
 TIME.

167
00:07:30,197 --> 00:07:31,899
 SO THERE IS SOME EVIDENCE OF

168
00:07:31,899 --> 00:07:33,734
 THIS IN MOUSE STUDIES.

169
00:07:33,734 --> 00:07:35,303
 WE'RE STILL TRYING TO

170
00:07:35,303 --> 00:07:37,171
 UNDERSTAND EXACTLY THE SIGNALS

171
00:07:37,171 --> 00:07:39,073
 THAT ALLOW THESE MICE TO GET

172
00:07:39,073 --> 00:07:41,509
 IN THE TISSUES AND IT WAS

173
00:07:41,509 --> 00:07:42,877
 STRIKING TO HAVE IT KIND OF

174
00:07:42,877 --> 00:07:44,845
 IDEA GOING BECAUSE IT REMINDED

175
00:07:44,845 --> 00:07:47,014
 US OF COURSE HOW T CELLS

176
00:07:47,014 --> 00:07:52,787
 DIFFERENTIATE AND THIS HAPPENS

177
00:07:52,787 --> 00:07:55,556
 IN LATIN AMERICA -- LYMPHOID

178
00:07:55,556 --> 00:07:57,491
 TISSUES AND WE KNOW THIS VERY

179
00:07:57,491 --> 00:07:59,727
 WELL SO WE LOOKED AT THE

180
00:07:59,727 --> 00:08:01,796
 TISSUE WITH THE ILC BUT THIS

181
00:08:01,796 --> 00:08:04,332
 TIME AT THE TISSUE LEVEL.

182
00:08:04,332 --> 00:08:07,635
 SO THE IDEA YOU HAVE THE ILC

183
00:08:07,635 --> 00:08:10,371
 AND TISSUE AND ENTERING

184
00:08:10,371 --> 00:08:11,639
 APPROPRIATELY IN PROGENY IS

185
00:08:11,639 --> 00:08:14,141
 THE MODEL WE'RE WORKING ON.

186
00:08:14,141 --> 00:08:16,077
 SO WHAT KIND OF SITUATION DO

187
00:08:16,077 --> 00:08:22,917
 WE HAVE WITH THE ILCS THAT ARE

188
00:08:22,917 --> 00:08:24,719
 KNIFE EVE?

189
00:08:24,719 --> 00:08:35,296
 THEY ARE LYMPHOID CELLS, THEY

190
00:08:40,501 --> 00:08:45,106
 DON'T HAVE MUCH CD7, THEY

191
00:08:45,106 --> 00:08:47,842
 DON'T HAVE ANY CLEAR METABOLIC

192
00:08:47,842 --> 00:08:49,810
 STATUS AND WHEN YOU START

193
00:08:49,810 --> 00:08:53,748
 USING THEM, YOU FIND THE

194
00:08:53,748 --> 00:08:57,151
 ILCP'S HAVE VERY LITTLE

195
00:08:57,151 --> 00:08:59,286
 ACTIVITY ALONG THE MAJOR

196
00:08:59,286 --> 00:09:01,055
 METABOLIC PATHWAYS.

197
00:09:01,055 --> 00:09:05,926
 SO HERE YOU HAVE THE T CELLS

198
00:09:05,926 --> 00:09:08,295
 TRANSCRIPTIONALLY IN TERMS OF

199
00:09:08,295 --> 00:09:09,563
 THE DIFFERENT PATHWAYS AND

200
00:09:09,563 --> 00:09:10,931
 FATTY ACIDS AND YOU CAN SEE

201
00:09:10,931 --> 00:09:13,234
 THEY ARE PRETTY MUCH BLACK

202
00:09:13,234 --> 00:09:20,107
 ACROSS THE BOARD AND LAURA

203
00:09:20,107 --> 00:09:22,910
 SIRACHE WHO DID VERY NICE WORK

204
00:09:22,910 --> 00:09:25,946
 AND YOU CAN SEE THEY ARE

205
00:09:25,946 --> 00:09:29,617
 STAINED FOR MIGHT MITOCHONDRIA

206
00:09:29,617 --> 00:09:32,787
 THAT ARE HIGHLY ACTIVE AND

207
00:09:32,787 --> 00:09:33,788
 POLARIZED BUT NONCONSISTENT.

208
00:09:33,788 --> 00:09:35,322
 SO THESE CELLS ARE WAITING TO

209
00:09:35,322 --> 00:09:37,358
 GET SIGNALS AND WAITING TO

210
00:09:37,358 --> 00:09:41,095
 TURN INTO MATURE ILC'S SO OUR

211
00:09:41,095 --> 00:09:43,030
 MODEL IS AGAIN BUILT AROUND

212
00:09:43,030 --> 00:09:44,432
 THIS T CELL PERSPECTIVE.

213
00:09:44,432 --> 00:09:47,001
 WE LIKE TO THINK WE MIGHT USE

214
00:09:47,001 --> 00:09:50,571
 THE SAME RULES T CELLS USE TO

215
00:09:50,571 --> 00:09:53,841
 DEVELOP INTO A PROGENY SO WE

216
00:09:53,841 --> 00:09:56,444
 POSTULATE THEY MAY HAVE A

217
00:09:56,444 --> 00:09:59,480
 NAIVE CELL, KNOW THERE IS A

218
00:09:59,480 --> 00:10:02,583
 REPOSSIBLE TORE CELL THEY NEED

219
00:10:02,583 --> 00:10:05,753
 TO STAY ALIVE, WE CAN IDENTIFY

220
00:10:05,753 --> 00:10:08,355
 THEM AND THEY RECEIVE SIGNAL 1

221
00:10:08,355 --> 00:10:13,294
 AND SIGNAL 2 THROUGH THIS ILC

222
00:10:13,294 --> 00:10:15,596
 RECEPTOR, COSTIMULATION, THAT

223
00:10:15,596 --> 00:10:18,466
 WOULD GENERATE THE EXPRESSION

224
00:10:18,466 --> 00:10:22,703
 AND WE KNOW THAT HAPPENS

225
00:10:22,703 --> 00:10:27,208
 ACTUALLY, WHEN WE TRIGGER THE

226
00:10:27,208 --> 00:10:30,611
 CELLS, THEY PRIVILEGE RATE

227
00:10:30,611 --> 00:10:31,445
 CLONALLLY.

228
00:10:31,445 --> 00:10:34,548
 NOW THE QUESTION HAPPENS WHAT

229
00:10:34,548 --> 00:10:36,784
 HAPPENS WHEN THEY ARE INVOLVED

230
00:10:36,784 --> 00:10:37,952
 IN THE REGENERATION PROCESS

231
00:10:37,952 --> 00:10:41,889
 AND HOPE TO GET THAT IN A

232
00:10:41,889 --> 00:10:46,560
 HUMAN SETTING AND SO WE LOOK

233
00:10:46,560 --> 00:10:53,501
 AT THE STUDY BY JOHN WHO HAS A

234
00:10:53,501 --> 00:10:54,468
 ROW -- ROBUST CULTURE SYSTEM

235
00:10:54,468 --> 00:10:56,070
 WITH THE CELLS AND TRY TO

236
00:10:56,070 --> 00:10:58,873
 PROCESS THEM AT A MOLECULAR

237
00:10:58,873 --> 00:10:59,173
 LEVEL.

238
00:10:59,173 --> 00:11:01,475
 SO I WILL SHIFT HERE AND TALK

239
00:11:01,475 --> 00:11:02,676
 ABOUT SOME WORK WE HAVE DONE

240
00:11:02,676 --> 00:11:04,345
 IN THE MOUSE AND THIS IS IN

241
00:11:04,345 --> 00:11:04,945
 THE GUT.

242
00:11:04,945 --> 00:11:06,213
 WE HAVE BEEN INTERESTED IN

243
00:11:06,213 --> 00:11:09,884
 TRYING TO UNDERSTAND THE ROLE

244
00:11:09,884 --> 00:11:12,386
 OF MATURE ILCS WITH THEIR

245
00:11:12,386 --> 00:11:13,621
 PARTICIPATION IN DEFENSE

246
00:11:13,621 --> 00:11:14,021
 MECHANISMS.

247
00:11:14,021 --> 00:11:16,357
 WE KNOW THIS IS A VERY COMPLEX

248
00:11:16,357 --> 00:11:17,224
 ECOSYSTEM.

249
00:11:17,224 --> 00:11:19,026
 THERE ARE MANY CELL TYPES IN

250
00:11:19,026 --> 00:11:21,095
 THE BARRIERS.

251
00:11:21,095 --> 00:11:26,901
 ILC IS PLACED IN CONNECTION TO

252
00:11:26,901 --> 00:11:29,336
 THE PHAGOCYTES AND DIFFERENT

253
00:11:29,336 --> 00:11:31,205
 KINDS OF CYTOKINES MAPPED OUT.

254
00:11:31,205 --> 00:11:32,940
 BUT THIS PICTURE CAN BE

255
00:11:32,940 --> 00:11:35,576
 MISLEADING PAUSE YOU SEE --

256
00:11:35,576 --> 00:11:37,778
 BECAUSE YOU SEE THE ARROWS AND

257
00:11:37,778 --> 00:11:39,613
 YOU THINK THESE THINGS ARE

258
00:11:39,613 --> 00:11:42,216
 MOVING AROUND IN A SECTIONAL

259
00:11:42,216 --> 00:11:44,885
 WAY BUT YOU NEED PROOF THAT

260
00:11:44,885 --> 00:11:47,254
 THAT IS ACTUALLY HAPPENING.

261
00:11:47,254 --> 00:11:54,695
 SO WE WERE INTERESTED IN THESE

262
00:11:54,695 --> 00:11:56,664
 PICTOGRAMS AND WE HAVE AN

263
00:11:56,664 --> 00:11:58,666
 EXPERT NEARBY, MANY OF YOU

264
00:11:58,666 --> 00:12:02,703
 KNOW HIM, AND HE HOOKED UP

265
00:12:02,703 --> 00:12:05,606
 WITH INDIVIDUALS IN THE LAB

266
00:12:05,606 --> 00:12:08,843
 INCLUDING A PH.D. STUDENT, AND

267
00:12:08,843 --> 00:12:15,716
 ONE HELPING OUT FROM FELIPE'S

268
00:12:15,716 --> 00:12:18,152
 LAB, THEY LOOKED AT THESE

269
00:12:18,152 --> 00:12:20,120
 CELLS IN MICE IN THE GUT.

270
00:12:20,120 --> 00:12:21,589
 NOW, THIS IS COMPLICATED BUT

271
00:12:21,589 --> 00:12:22,990
 THEY WERE ABLE TO GET

272
00:12:22,990 --> 00:12:24,158
 BEAUTIFUL MOVIES AND I WILL

273
00:12:24,158 --> 00:12:25,459
 SHARE THEM WITH YOU.

274
00:12:25,459 --> 00:12:27,161
 THE QUESTION IS DO THESE CELLS

275
00:12:27,161 --> 00:12:28,796
 MOVE AND WE MIGHT IMAGINE THEY

276
00:12:28,796 --> 00:12:31,432
 DO BECAUSE IN THE END, WE

277
00:12:31,432 --> 00:12:33,000
 THINK OF ILCS MOVING AROUND

278
00:12:33,000 --> 00:12:34,902
 AND BEING PART OF THE DEFENSE

279
00:12:34,902 --> 00:12:37,638
 MECHANISM BUT IF THEY DO MOVE,

280
00:12:37,638 --> 00:12:40,274
 HOW IS IT REGULATED AND CHANGE

281
00:12:40,274 --> 00:12:42,042
 MAYBE WHEN YOU HAVE DIFFERENT

282
00:12:42,042 --> 00:12:43,143
 TYPES OF CHALLENGES?

283
00:12:43,143 --> 00:12:45,112
 SO HERE IS SOME IMAGES.

284
00:12:45,112 --> 00:12:47,314
 I WON'T GET EXACTLY INTO THE

285
00:12:47,314 --> 00:12:49,316
 MODEL BUT IF YOU HAVE

286
00:12:49,316 --> 00:12:54,922
 QUESTIONS THAT IS BUILT AROUND

287
00:12:54,922 --> 00:12:57,892
 THIS, THOSE THEN ALLOW YOU TO

288
00:12:57,892 --> 00:13:00,461
 TRACK THE ILC'S IN THE GUT.

289
00:13:00,461 --> 00:13:02,930
 SO IF YOU LOOK, YOU CAN SEE

290
00:13:02,930 --> 00:13:05,366
 THESE CELLS AND THEY TO MOVE

291
00:13:05,366 --> 00:13:06,400
 AROUND ALTHOUGH COMPARED TO

292
00:13:06,400 --> 00:13:08,602
 THE BLUE CELLS WHICH ARE T

293
00:13:08,602 --> 00:13:10,471
 CELLS THAT WE MARKED

294
00:13:10,471 --> 00:13:11,572
 INDEPENDENTLY, THEY ARE REALLY

295
00:13:11,572 --> 00:13:12,606
 NOT MOVING AS MUCH.

296
00:13:12,606 --> 00:13:15,509
 SO THEY ARE NOT AS MOTILE AS

297
00:13:15,509 --> 00:13:17,711
 WE HAVE IN T CELLS.

298
00:13:17,711 --> 00:13:23,684
 NOW, IF YOU LOOK IN THE CRIPS

299
00:13:23,684 --> 00:13:25,452
 WHERE YOU HAVE THE PATCHES,

300
00:13:25,452 --> 00:13:27,187
 THEY ARE NOTED BY THE GROUPS

301
00:13:27,187 --> 00:13:29,356
 BUT THESE ARE APART AND NOT

302
00:13:29,356 --> 00:13:32,459
 MOVING AT ALL.

303
00:13:32,459 --> 00:13:34,895
 SO THE ILCS THAT ARE PRESENT

304
00:13:34,895 --> 00:13:37,564
 IN TWO PARTS IN THE GUT HAVE

305
00:13:37,564 --> 00:13:38,399
 TWO DIFFERENT TYPES OF

306
00:13:38,399 --> 00:13:40,534
 ACTIVITY AND THAT CAN BE

307
00:13:40,534 --> 00:13:40,935
 QUANTITATED.

308
00:13:40,935 --> 00:13:42,403
 THE T CELLS ARE IN THIS GROUP

309
00:13:42,403 --> 00:13:44,939
 AND YOU CAN SEE THEY ARE

310
00:13:44,939 --> 00:13:49,209
 MOVING AROUND IN DIFFERENT

311
00:13:49,209 --> 00:13:49,610
 DIRECTIONS.

312
00:13:49,610 --> 00:13:52,379
 THE I WILL HAVE LOUSE ILCS ARE

313
00:13:52,379 --> 00:13:54,682
 HERE, NOT DOING MUCH BUT DOING

314
00:13:54,682 --> 00:13:58,519
 SOME AND THESE ARE THE ONE IN

315
00:13:58,519 --> 00:13:59,086
 THE CRIP.

316
00:13:59,086 --> 00:14:00,888
 SO IF YOU LOOK AT THIS

317
00:14:00,888 --> 00:14:04,425
 BEHAVIOR, YOU CAN SEE MOST OF

318
00:14:04,425 --> 00:14:07,194
 THE ILCS ARE ARRESTED AND THE

319
00:14:07,194 --> 00:14:08,462
 T CELLS ARE MOVING AROUND.

320
00:14:08,462 --> 00:14:11,465
 SO THIS IS A BIT OF SURPRISE,

321
00:14:11,465 --> 00:14:15,169
 T CELLS MOVING ILC'S STUFF.

322
00:14:15,169 --> 00:14:16,770
 AND WHY WOULD THAT BE?

323
00:14:16,770 --> 00:14:19,840
 WE DON'T REALLY HAVE AN ANSWER

324
00:14:19,840 --> 00:14:21,842
 BUT WE HAVE SOME THOUGHTS AND

325
00:14:21,842 --> 00:14:26,213
 WILL SHARE THEM WITH YOU.

326
00:14:26,213 --> 00:14:28,115
 CAN THE ILC'S MOVE?

327
00:14:28,115 --> 00:14:30,918
 WELL, WE SET THIS UP AND IF WE

328
00:14:30,918 --> 00:14:32,353
 USE THIS MODEL, WE CAN SEE

329
00:14:32,353 --> 00:14:34,288
 AGAIN THE CELLS ARE NOT REALLY

330
00:14:34,288 --> 00:14:35,723
 MOVING IN THE I WILL HAVE

331
00:14:35,723 --> 00:14:38,525
 LOUSE BUT IF WE ACTIVATE THEM

332
00:14:38,525 --> 00:14:40,494
 WITH INFLAMMATION AND THAT WE

333
00:14:40,494 --> 00:14:50,337
 CAN DO BY PUTTING FLAGO.J. 

334
00:14:50,337 --> 00:14:51,939
 LLIN -- FLAGELLIN IN THE

335
00:14:51,939 --> 00:14:54,341
 SYSTEM AND YOU CAN DOCUMENT IT

336
00:14:54,341 --> 00:14:55,576
 AND SEE THEY HAVE CHANGED FROM

337
00:14:55,576 --> 00:14:59,146
 ARRESTED TO MOVING AND

338
00:14:59,146 --> 00:15:01,682
 INCREASED VELOCITY AND

339
00:15:01,682 --> 00:15:02,316
 PLACEMENT.

340
00:15:02,316 --> 00:15:06,854
 SO ILCS CAN MOVE AROUND, IT IS

341
00:15:06,854 --> 00:15:10,157
 JUST UNDER HOMEO STATIC

342
00:15:10,157 --> 00:15:11,592
 CONDITIONS THAT THEY ARE NOT

343
00:15:11,592 --> 00:15:14,928
 AND WHAT DOES IT TAKE TO GET

344
00:15:14,928 --> 00:15:15,529
 THEM GOING.

345
00:15:15,529 --> 00:15:18,565
 SO WHY WOULD THEY BE

346
00:15:18,565 --> 00:15:19,967
 RESTRICTED IN HOMEOSTASIS AND

347
00:15:19,967 --> 00:15:27,374
 WHY WOULD YOU NEED THEM TO BE

348
00:15:27,374 --> 00:15:28,308
 MOVING?

349
00:15:28,308 --> 00:15:38,886
 SO IF YOU TAKE AWAY THE CELLS,

350
00:15:43,524 --> 00:15:49,496
 LOOK AT ILC3'S, THEY ARE 

351
00:15:49,496 --> 00:15:52,066
 MOTILE AND MAKING IMMUNITY.

352
00:15:52,066 --> 00:15:54,802
 SO THESE ARE CHARACTERISTIC ON

353
00:15:54,802 --> 00:15:58,205
 ADAPTING IMMUNITY IN THE

354
00:15:58,205 --> 00:15:58,539
 SYSTEM.

355
00:15:58,539 --> 00:15:59,907
 SO WHAT IS INVOLVED?

356
00:15:59,907 --> 00:16:01,942
 IT IS INTERESTING, YOU CAN SET

357
00:16:01,942 --> 00:16:04,278
 UP TYPES OF OTHER MUTANTS AND

358
00:16:04,278 --> 00:16:05,479
 HERE WE HAVE THE T CELL AND

359
00:16:05,479 --> 00:16:07,981
 WHEN YOU PUT THE T CELL IN THE

360
00:16:07,981 --> 00:16:15,756
 SYSTEM, NOW YOU TURN THE

361
00:16:15,756 --> 00:16:18,425
 MOBILE ILC3'S AND THE T CELLS

362
00:16:18,425 --> 00:16:19,426
 SHUT THEM DOWN.

363
00:16:19,426 --> 00:16:21,995
 SO WHY IS THIS HAPPENING?

364
00:16:21,995 --> 00:16:23,297
 WE LOOKED AT THE INTERACTION

365
00:16:23,297 --> 00:16:27,101
 AND CAME UPON A MATCH AND THAT

366
00:16:27,101 --> 00:16:31,438
 WAS EXACTLY CCR9 WHICH IS 

367
00:16:31,438 --> 00:16:33,240
 EXPRESSED ON ILC3 AND ON T

368
00:16:33,240 --> 00:16:35,075
 CELLS IN THE GUT ARE ACTUALLY

369
00:16:35,075 --> 00:16:39,713
 RELEVANT RANT AND IT IS THE

370
00:16:39,713 --> 00:16:41,548
 CCR9 EXPRESSION IN THE GUT

371
00:16:41,548 --> 00:16:46,386
 THAT IS REGULATING THE ILC3'S

372
00:16:46,386 --> 00:16:49,723
 SO WE EXPRESSED THAT BY

373
00:16:49,723 --> 00:16:52,192
 PUTTING ABELATED T CELLS IN

374
00:16:52,192 --> 00:16:55,762
 THE SYSTEM AND THOSE ILC3'S

375
00:16:55,762 --> 00:16:57,731
 ARE NOW ABLE TO MOVE AROUND

376
00:16:57,731 --> 00:16:59,333
 WHERE IF YOU PUT BACK IN THE

377
00:16:59,333 --> 00:17:01,335
 SYSTEM NORMAL T CELLS, YOU

378
00:17:01,335 --> 00:17:02,202
 SHUT THEM DOWN.

379
00:17:02,202 --> 00:17:05,873
 SO THIS STORY IS BASICALLY

380
00:17:05,873 --> 00:17:07,107
 SUMMARIZED HERE.

381
00:17:07,107 --> 00:17:08,442
 IT BUILDS ON PREVIOUS

382
00:17:08,442 --> 00:17:11,845
 OBSERVATIONS MADE HERE AT NIH

383
00:17:11,845 --> 00:17:15,749
 CONCERNING THE ACTIVE ILC3'S

384
00:17:15,749 --> 00:17:18,218
 IN THE EARLY NATAL PERIOD

385
00:17:18,218 --> 00:17:20,454
 WHERE THEY ARE COMING INTO

386
00:17:20,454 --> 00:17:21,722
 PLAY BEFORE THE T CELLS ARE

387
00:17:21,722 --> 00:17:23,357
 FOUND IN THE GUT.

388
00:17:23,357 --> 00:17:25,726
 THESE ARE HIGHLY ACTIVE,

389
00:17:25,726 --> 00:17:27,628
 CYTOKINE STIMULATED AND ACTING

390
00:17:27,628 --> 00:17:30,631
 VERY STRONGLY WITH THE

391
00:17:30,631 --> 00:17:31,165
 EPITHELIAL BARRIER.

392
00:17:31,165 --> 00:17:33,400
 THEN THE T CELLS COME IN AND

393
00:17:33,400 --> 00:17:36,370
 SHUT THAT DOWN, AND THEY SHUT

394
00:17:36,370 --> 00:17:38,639
 THAT DOWN APPARENTLY THROUGH

395
00:17:38,639 --> 00:17:42,142
 THEIR ABILITY TO COMPETE WITH

396
00:17:42,142 --> 00:17:45,078
 THE ILC'S WITH CCL25 WHICH

397
00:17:45,078 --> 00:17:48,715
 THEN TURNS THEM INTO ILC3'S

398
00:17:48,715 --> 00:17:50,918
 THAT ARE IMMOBILE AND NOT

399
00:17:50,918 --> 00:17:52,286
 ANYMORE CONTROLLING IN THE

400
00:17:52,286 --> 00:17:52,819
 INTESTINAL BARRIER.

401
00:17:52,819 --> 00:17:55,656
 NOW THAT IS NOT A PERMANENT

402
00:17:55,656 --> 00:17:56,023
 STATE.

403
00:17:56,023 --> 00:17:58,692
 THAT STATE CAN BE ACTIVATED

404
00:17:58,692 --> 00:18:02,529
 AND THEY CAN TURN INTO ILC3'S

405
00:18:02,529 --> 00:18:04,631
 AFTER BEING ACTIVATED BY THE

406
00:18:04,631 --> 00:18:05,098
 RELEVANT SIGNAL.

407
00:18:05,098 --> 00:18:07,935
 SO WE CAN TALK ABOUT WHY THEY

408
00:18:07,935 --> 00:18:10,204
 MIGHT NOT BE MOVING AROUND AT

409
00:18:10,204 --> 00:18:12,039
 THIS STAGE BUT I WILL LEAVE

410
00:18:12,039 --> 00:18:13,173
 THAT FOR QUESTIONS AND IN THE

411
00:18:13,173 --> 00:18:16,643
 LAST MINUTE OR TWO, SOME

412
00:18:16,643 --> 00:18:19,413
 QUESTIONS RELATED TO 

413
00:18:19,413 --> 00:18:20,981
 ADAPTATION FOR ILC3'S AND THIS

414
00:18:20,981 --> 00:18:26,353
 IS WHERE THE ILC3'S GET

415
00:18:26,353 --> 00:18:27,154
 ACTIVATED AT MULTIPLE TIMES

416
00:18:27,154 --> 00:18:30,324
 AND WE KNOW THAT HAPPENS IN

417
00:18:30,324 --> 00:18:32,392
 THE GUT, ILC3'S MAY BE

418
00:18:32,392 --> 00:18:33,760
 RECEIVING SIGNALS THROUGH THE

419
00:18:33,760 --> 00:18:35,062
 LIFETIME OF THE ORGANISM.

420
00:18:35,062 --> 00:18:37,731
 WE KNOW THAT CAN ACTIVATE T

421
00:18:37,731 --> 00:18:39,299
 CELLS HAVING MULTIPLE

422
00:18:39,299 --> 00:18:40,601
 ENCOUNTERS WITH INFECTIONS BUT

423
00:18:40,601 --> 00:18:43,337
 THE QUESTION IS WHAT HAPPENS

424
00:18:43,337 --> 00:18:45,639
 WITH THE ILC3'S IN THIS, DO

425
00:18:45,639 --> 00:18:49,476
 THEY HAVE ANY LONG-TERM IMPACT

426
00:18:49,476 --> 00:18:51,612
 OVER A LIFETIME, IS THERE AN

427
00:18:51,612 --> 00:18:54,147
 IMPACT ON THEIR CAPACITY TO

428
00:18:54,147 --> 00:18:55,482
 DEFEND THE BARRIER AND IF THEY

429
00:18:55,482 --> 00:18:57,217
 DO, WHAT IS INVOLVED?

430
00:18:57,217 --> 00:19:02,322
 SO NOT VERY SIMPLE TO TO THIS.

431
00:19:02,322 --> 00:19:09,663
 WE USED THIS MODEL TO LOOK AT

432
00:19:09,663 --> 00:19:15,035
 ILC3 PRODUCTIVITY AND ACTIVATE

433
00:19:15,035 --> 00:19:16,703
 IL22 PRODUCTION WHICH IS

434
00:19:16,703 --> 00:19:23,844
 IMPORTANT IN THE MOUSE MODEL, 

435
00:19:23,844 --> 00:19:25,646
 THAT THEN ACTIVATES A SYSTEM

436
00:19:25,646 --> 00:19:27,047
 THAT IS CHALLENGED AND A LOT

437
00:19:27,047 --> 00:19:28,315
 OF THINGS GOING ON.

438
00:19:28,315 --> 00:19:33,153
 SO WE SET UP A SYSTEM TO MAKE 

439
00:19:33,153 --> 00:19:38,625
 THIS TARGETED THROUGH ILC AND

440
00:19:38,625 --> 00:19:40,394
 ILC3'S IN PARTICULAR.

441
00:19:40,394 --> 00:19:46,466
 WE INFECT THE MICE WITH

442
00:19:46,466 --> 00:19:47,968
 CITROBACTER, THEN TREAT THEM A

443
00:19:47,968 --> 00:19:58,412
 FEW DAYS LATER WITH AN

444
00:20:04,251 --> 00:20:06,153
 ANTIBIOTIC, AND WE LOOK AT

445
00:20:06,153 --> 00:20:08,655
 WHAT HAPPENS LATER IF YOU

446
00:20:08,655 --> 00:20:13,060
 EXPOSE THOSE MICE TO

447
00:20:13,060 --> 00:20:15,028
 CITROBACTIN, SO HERE IS THE

448
00:20:15,028 --> 00:20:18,965
 CONTROL, WE COLONIZE THE MICE,

449
00:20:18,965 --> 00:20:21,401
 GET THE CITROBACTIN IN THERE,

450
00:20:21,401 --> 00:20:25,472
 GET SOME ACTIVATION OF THE 

451
00:20:25,472 --> 00:20:27,641
 ILC, PARTICULARLY ILC3'S, NOW

452
00:20:27,641 --> 00:20:29,009
 YOU CLEAR IT, ACTIVATE THE

453
00:20:29,009 --> 00:20:30,444
 CELLS WITH A SECOND EXPOSURE

454
00:20:30,444 --> 00:20:35,882
 AND NOW THE ILC3'S HAVE THIS

455
00:20:35,882 --> 00:20:36,483
 INCREDIBLE ADDITIONAL

456
00:20:36,483 --> 00:20:38,218
 FUNCTIONAL CAPACITY IN THESE

457
00:20:38,218 --> 00:20:38,919
 MATTERS.

458
00:20:38,919 --> 00:20:42,089
 WE CALL THEM TRAINED ILC'S SO

459
00:20:42,089 --> 00:20:43,256
 SOMEHOW THEY HAVE WORKED OUT

460
00:20:43,256 --> 00:20:46,727
 AND HAVE SOME MUSCLE AND THEY

461
00:20:46,727 --> 00:20:47,527
 CHARACTERIZE IN DIFFERENT

462
00:20:47,527 --> 00:20:49,396
 LEVELS, I WILL SHOW THAT HERE,

463
00:20:49,396 --> 00:20:51,264
 THEY HAVE A LOT MORE

464
00:20:51,264 --> 00:20:52,366
 PRODUCTION, THEY PERSIST IN

465
00:20:52,366 --> 00:20:53,967
 THE TISSUES, WE HAVE DONE THAT

466
00:20:53,967 --> 00:20:55,669
 IN MAPPING.

467
00:20:55,669 --> 00:21:00,640
 THEY CAN EVEN BE GENERATED IN

468
00:21:00,640 --> 00:21:04,411
 RAG MICE AND THEY ALLOW FOR

469
00:21:04,411 --> 00:21:06,747
 PROTECTION AGAINST OTHER KINDS

470
00:21:06,747 --> 00:21:09,416
 OF PATHOGENS SO THEY ALLOW

471
00:21:09,416 --> 00:21:11,752
 CROSS PROTECTION AND WE CAN

472
00:21:11,752 --> 00:21:12,252
 TRANSFER THAT.

473
00:21:12,252 --> 00:21:13,653
 SO THIS IS THE END OF THE

474
00:21:13,653 --> 00:21:14,821
 STORY, MAYBE THE BEGINNING FOR

475
00:21:14,821 --> 00:21:16,656
 SOME OTHER STORIES BUT IT

476
00:21:16,656 --> 00:21:20,961
 LOOKS LIKE THIS ENCOUNTER WITH

477
00:21:20,961 --> 00:21:21,995
 CITROBACTER REPROGRAMS THE

478
00:21:21,995 --> 00:21:31,371
 CELLS CERTAINLY AT THE LEVEL 

479
00:21:31,371 --> 00:21:37,377
 OF THEIR METABOLISM, THE OX

480
00:21:37,377 --> 00:21:44,718
 PLUS PRO LIVE RATES -- OX PH

481
00:21:44,718 --> 00:21:45,786
 OS PROLIFERATES AND THAT

482
00:21:45,786 --> 00:21:49,356
 ALLOWS THEM TO HAVE A BETTER

483
00:21:49,356 --> 00:21:50,957
 AND PERHAPS FASTER RESPONSE

484
00:21:50,957 --> 00:21:51,658
 DURING THE LIFETIME FOR

485
00:21:51,658 --> 00:21:52,893
 PROTECTION OF THE INDIVIDUAL.

486
00:21:52,893 --> 00:21:54,227
 SO THIS IS THE SUMMARY AND I

487
00:21:54,227 --> 00:21:55,595
 DON'T THINK I NEED TO GO

488
00:21:55,595 --> 00:21:57,030
 THROUGH THIS IN DETAIL.

489
00:21:57,030 --> 00:21:58,098
 THERE ARE STILL SOME AREAS

490
00:21:58,098 --> 00:22:00,100
 THAT ARE IMPORTANT TO

491
00:22:00,100 --> 00:22:01,268
 UNDERSTAND.

492
00:22:01,268 --> 00:22:04,237
 THE PLASTICITY OF THE ILC3'S

493
00:22:04,237 --> 00:22:06,006
 ARE SOMETHING WE STILL HAVE TO

494
00:22:06,006 --> 00:22:08,041
 WORK ON, WE HAVE LEARNED A LOT

495
00:22:08,041 --> 00:22:18,585
 HOW THEY ARE INVOLVED IN THE

496
00:22:20,153 --> 00:22:20,720
 STRUCTURES.

497
00:22:20,720 --> 00:22:22,622
 SO I WILL STOP HERE AND

498
00:22:22,622 --> 00:22:27,494
 ACKNOWLEDGE PEOPLE WHO DID 

499
00:22:27,494 --> 00:22:29,429
 THIS WORK.

500
00:22:29,429 --> 00:22:30,964
 AND OUR FUNDERS, AND I WILL BE

501
00:22:30,964 --> 00:22:33,900
 HAPPY TO TAKE QUESTIONS.

502
00:22:33,900 --> 00:22:40,073
 [APPLAUSE] 

503
00:22:40,073 --> 00:22:48,548
 >> LOOKING FOR SOMEONE

504
00:22:48,548 --> 00:22:48,882
 YOUNGER.

505
00:22:48,882 --> 00:22:49,249
 [LAUGHTER]

506
00:22:49,249 --> 00:22:50,450
 >> HI, VERY GREAT TALK
AND

507
00:22:50,450 --> 00:22:51,351
 USEFUL INFORMATION.

508
00:22:51,351 --> 00:22:55,021
 SO I HAVE COUPLE OF QUESTIONS

509
00:22:55,021 --> 00:23:01,995
 BUT SO YOU SHOW THAT THE MOUSE

510
00:23:01,995 --> 00:23:04,197
 SEASON WHERE THEY EXIST AND

511
00:23:04,197 --> 00:23:06,566
 YOU SIGNAL 1, 2, 3 AS YOU ARE

512
00:23:06,566 --> 00:23:08,635
 IDENTIFYING TO BECOME

513
00:23:08,635 --> 00:23:09,169
 ACTIVATED ILC.

514
00:23:09,169 --> 00:23:12,806
 BUT I WAS WONDERING IN TERMS

515
00:23:12,806 --> 00:23:14,641
 OF METABOLISM, THEY ARE QUITE

516
00:23:14,641 --> 00:23:24,751
 DISSIMILAR TO WHAT WE THINK OF

517
00:23:24,751 --> 00:23:25,285
 ABOUT METABOLISM.

518
00:23:25,285 --> 00:23:28,355
 SO YOU SHOW THEY HAVE DURING

519
00:23:28,355 --> 00:23:34,561
 THE PRIMARY FUNCTION,

520
00:23:34,561 --> 00:23:37,364
 GLYCOLISIS AND IN THE

521
00:23:37,364 --> 00:23:39,833
 SECONDARY INFECTION, THEY

522
00:23:39,833 --> 00:23:41,368
 SWITCH TO OXPHOS.

523
00:23:41,368 --> 00:23:43,670
 >> THEY HAVE THE OXPHOS
IN THE

524
00:23:43,670 --> 00:23:45,505
 PRIMARY AND THAT IS

525
00:23:45,505 --> 00:23:45,906
 PERSISTENT.

526
00:23:45,906 --> 00:23:47,274
 THE ACTIVATION IN THIS CONTEXT

527
00:23:47,274 --> 00:23:48,441
 IS NOT VERY STRONG.

528
00:23:48,441 --> 00:23:50,777
 WE LOOKED AT THAT AND THEY

529
00:23:50,777 --> 00:23:57,484
 DON'T HAVE A DRAMATIC INCREASE

530
00:23:57,484 --> 00:23:58,318
 IN GLYCOLISIS.

531
00:23:58,318 --> 00:24:01,354
 NOW HUMANS DO AND WHEN THEY

532
00:24:01,354 --> 00:24:07,394
 GET ACTIVATED WITH ILC2'S THEY

533
00:24:07,394 --> 00:24:10,697
 GET VERY ACTIVE.

534
00:24:10,697 --> 00:24:21,241
 SO EVERY TISSUE IS DIFFERENT

535
00:24:24,978 --> 00:24:26,746
 AND ACTIVATE DIFFERENTLY.

536
00:24:26,746 --> 00:24:35,121
 >> SHORT T QUESTION.

537
00:24:35,121 --> 00:24:38,925
 T CELLS, IF THEY ARE ENOUGH TO

538
00:24:38,925 --> 00:24:41,728
 KNOCK AROUND, PROLIFERATE ILC.

539
00:24:41,728 --> 00:24:44,297
 HOW DID THAT HAPPEN IN THE

540
00:24:44,297 --> 00:24:44,931
 CONTROL?

541
00:24:44,931 --> 00:24:47,334
 >> THEY DO GET
PROLIFERATION

542
00:24:47,334 --> 00:24:49,803
 BUT NOWHERE NEAR THE AMOUNT OF

543
00:24:49,803 --> 00:24:50,303
 T CELLS.

544
00:24:50,303 --> 00:24:51,371
 >> BUT I WAS ASKING ABOUT
THE

545
00:24:51,371 --> 00:24:52,806
 MEMORIES THAT YOU WERE --

546
00:24:52,806 --> 00:24:54,441
 >> THE MEMORY CELLS DO
CREATE

547
00:24:54,441 --> 00:24:57,444
 A LITTLE BIT MORE AND IN THAT

548
00:24:57,444 --> 00:24:59,179
 CONTEXT, YOU KNOW, WE DON'T

549
00:24:59,179 --> 00:25:05,585
 KNOW EXACTLY WHAT DRIVES THAT.

550
00:25:05,585 --> 00:25:09,356
 >> SO I HAVE A
PHILOSOPHICAL

551
00:25:09,356 --> 00:25:15,462
 QUESTION AND THE QUESTION IS

552
00:25:15,462 --> 00:25:21,735
 WE HAVE IL C1, ILC2, ILC3 AND

553
00:25:21,735 --> 00:25:32,245
 WHY DON'T WE HAVE PHOS3 TO

554
00:25:32,979 --> 00:25:33,179
 ILC?

555
00:25:33,179 --> 00:25:33,680
 >> GOOD QUESTION.

556
00:25:33,680 --> 00:25:36,383
 ACTUALLY THERE WAS ONE REPORT

557
00:25:36,383 --> 00:25:38,251
 ON A ILC RAG THAT WAS

558
00:25:38,251 --> 00:25:40,220
 PUBLISHED BUT LOOKS MORE LIKE

559
00:25:40,220 --> 00:25:42,922
 A ILC2 THAT HAS A BIT OF HYPER

560
00:25:42,922 --> 00:25:43,323
 ACTIVATION.

561
00:25:43,323 --> 00:25:44,624
 SO THE QUESTION IS WHAT

562
00:25:44,624 --> 00:25:46,426
 REGULATES THEM AND WHAT IS

563
00:25:46,426 --> 00:25:48,228
 NEEDED TO REGULATE THEM AND SO

564
00:25:48,228 --> 00:25:54,601
 COMPARED TO T CELLS WHICH HAVE

565
00:25:54,601 --> 00:25:55,769
 THIS AUTONOMOUS IL3 PRODUCTION

566
00:25:55,769 --> 00:25:57,971
 AND SOME WAY OF PROLIFERATING

567
00:25:57,971 --> 00:26:00,173
 IN SOME WAY, OBVIOUSLY YOU

568
00:26:00,173 --> 00:26:04,678
 HAVE TO HAVE A REGULATORY

569
00:26:04,678 --> 00:26:05,045
 MECHANISM.

570
00:26:05,045 --> 00:26:06,446
 ILCS DON'T HAVE THAT SO THEY

571
00:26:06,446 --> 00:26:10,417
 MAY NOT NEED THAT EXTRA LAYER 

572
00:26:10,417 --> 00:26:11,651
 VIA A DEDICATED CELL AND I

573
00:26:11,651 --> 00:26:13,853
 THINK SOME OF THE OTHER

574
00:26:13,853 --> 00:26:17,323
 FACTORS WHICH ARE PART OF

575
00:26:17,323 --> 00:26:18,224
 THEIR HOMEOSTASIS ARE LIMITED

576
00:26:18,224 --> 00:26:21,761
 AND THE SYSTEM IN GENERAL IS A

577
00:26:21,761 --> 00:26:24,364
 LITTLE MORE COMPACT AS WELL.

578
00:26:24,364 --> 00:26:25,298
 >> SO WONDERFUL TALK AND
I

579
00:26:25,298 --> 00:26:27,400
 HOPE YOU CAN HEAR ME, I AM

580
00:26:27,400 --> 00:26:29,669
 TRYING TO EAT THE MICROPHONE.

581
00:26:29,669 --> 00:26:30,837
 SO I WAS WONDERING IF YOU

582
00:26:30,837 --> 00:26:33,673
 COULD SAY A LITTLE BIT MORE

583
00:26:33,673 --> 00:26:35,341
 ABOUT THE TISSUE SPECIFICITY

584
00:26:35,341 --> 00:26:38,645
 WHEN IT COMES TO GENE PROFILES

585
00:26:38,645 --> 00:26:42,949
 THAT ARE SPECIAL IN ILC3'S

586
00:26:42,949 --> 00:26:46,886
 GOING TO A CERTAIN TISSUE BUT 

587
00:26:46,886 --> 00:26:48,288
 ONLY FOR ACTIVATION, FOR

588
00:26:48,288 --> 00:26:50,457
 REPAIR FUNCTIONS BECAUSE FOR A

589
00:26:50,457 --> 00:26:51,291
 NUMBER OF CELLS, THEY HAVE

590
00:26:51,291 --> 00:26:53,960
 BEEN SHOWN TO BE BASED ON THE

591
00:26:53,960 --> 00:26:54,594
 TISSUE --

592
00:26:54,594 --> 00:26:55,028
 >> ABSOLUTELY.

593
00:26:55,028 --> 00:26:55,962
 I THINK THERE HAVE BEEN A

594
00:26:55,962 --> 00:26:59,199
 NUMBER OF OTHER GROUPS THAT

595
00:26:59,199 --> 00:27:00,867
 HAVE CON BOOTED A LOT MORE

596
00:27:00,867 --> 00:27:02,969
 THAN US IN THAT DOMAIN AND

597
00:27:02,969 --> 00:27:04,938
 DON'T HAVE MUCH MORE TO SAY IN

598
00:27:04,938 --> 00:27:08,475
 ADDING TO THAT KNOWLEDGE BASE.

599
00:27:08,475 --> 00:27:10,143
 RICHARD LOXIE HAD A HUGE

600
00:27:10,143 --> 00:27:11,344
 IMPACT IN THAT AREA AND AGAIN

601
00:27:11,344 --> 00:27:13,880
 IT IS VERY TISSUE-SPECIFIC.

602
00:27:13,880 --> 00:27:15,415
 SO THE KINDS OF QUESTIONS

603
00:27:15,415 --> 00:27:17,817
 RELATED TO WHAT IS KNOWN IN

604
00:27:17,817 --> 00:27:19,052
 THE MOUSE AND TRANSLATING THAT

605
00:27:19,052 --> 00:27:20,620
 IN THE HUMAN IS AN IMPORTANT

606
00:27:20,620 --> 00:27:22,222
 AREA TO GO TO AND I THINK

607
00:27:22,222 --> 00:27:23,957
 PEOPLE SHOULD FOCUS IN ON

608
00:27:23,957 --> 00:27:25,525
 TRYING TO HAVE A DEEPER

609
00:27:25,525 --> 00:27:27,393
 UNDERSTANDING HOW THE CELLS

610
00:27:27,393 --> 00:27:29,929
 ARE TISSUE-SPECIFIC IN TERMS

611
00:27:29,929 --> 00:27:30,497
 OF PROPERTIES.

612
00:27:30,497 --> 00:27:31,765
 >> THE T CELLS STOPPING
THE

613
00:27:31,765 --> 00:27:35,835
 MOVEMENT OF THE ILC SUGGESTS

614
00:27:35,835 --> 00:27:41,407
 THAT THE T CELLS WORK SLOWLY.

615
00:27:41,407 --> 00:27:45,178
 DOES THE ILC HAVE THE ABILITY

616
00:27:45,178 --> 00:27:49,949
 TO PRODUCE THEIR OWN SITE

617
00:27:49,949 --> 00:27:50,583
 CANES --

618
00:27:50,583 --> 00:27:51,151
 [INDISCERNIBLE]

619
00:27:51,151 --> 00:27:51,851
 >>  WE INTRODUCED THEM TO
THE

620
00:27:51,851 --> 00:27:53,153
 TARGET AND DON'T UNDERSTAND

621
00:27:53,153 --> 00:27:53,920
 WHY.

622
00:27:53,920 --> 00:27:56,356
 YOU WOULD THINK IT WOULD BE

623
00:27:56,356 --> 00:27:57,290
 DETRIMENTAL TO HAVE THEM

624
00:27:57,290 --> 00:27:58,191
 CONTROLLING ALL THE TIME AND

625
00:27:58,191 --> 00:28:00,760
 THAT IS THE CASE IN THE RAG.

626
00:28:00,760 --> 00:28:02,929
 THESE CELLS ARE MOVING AROUND

627
00:28:02,929 --> 00:28:06,499
 AND THEN THE BORDER IS GETTING

628
00:28:06,499 --> 00:28:07,667
 BOMBARDED BASICALLY WITH 22

629
00:28:07,667 --> 00:28:10,336
 WHICH CAN, IF IT IS NOT IN A

630
00:28:10,336 --> 00:28:12,472
 CONTROLLED WAY, GENERATE THEN

631
00:28:12,472 --> 00:28:12,972
 TRANSFORMATION.

632
00:28:12,972 --> 00:28:14,240
 THAT HAS BEEN SHOWN IF YOU

633
00:28:14,240 --> 00:28:16,810
 TAKE AWAY THE BINDING PROTEIN

634
00:28:16,810 --> 00:28:17,510
 FOR INSTANCE.

635
00:28:17,510 --> 00:28:18,545
 SO MAYBE THE REASON THEY ARE

636
00:28:18,545 --> 00:28:20,079
 NOT MOVING IS TO PREVENT THAT.

637
00:28:20,079 --> 00:28:21,648
 BUT WHEN YOU HAVE THE CONTEXT

638
00:28:21,648 --> 00:28:23,082
 OF REPAIR AND YOU WANT TO HAVE

639
00:28:23,082 --> 00:28:25,185
 MORE AND YOU HAVE BASICALLY

640
00:28:25,185 --> 00:28:29,222
 THE RESERVE, THEN THE CELLS

641
00:28:29,222 --> 00:28:30,557
 MOVE AROUND DELIBERATE.

642
00:28:30,557 --> 00:28:32,458
 AND I HAVE DATA I DIDN'T SHOW

643
00:28:32,458 --> 00:28:34,828
 BUT IF YOU STOP THIS IN RAGS,

644
00:28:34,828 --> 00:28:37,564
 YOU ACTUALLY DO DECREASE THE

645
00:28:37,564 --> 00:28:38,698
 PERMEABILITY IN THE MEMBRANE

646
00:28:38,698 --> 00:28:41,634
 SO IT IS HAVING A POSITIVE

647
00:28:41,634 --> 00:28:50,276
 EFFECT IN THE MEMBRANE IN THE

648
00:28:50,276 --> 00:28:50,677
 RAG PATROL.

649
00:28:50,677 --> 00:28:54,447
 >> I HAVE A QUESTION ON
THE

650
00:28:54,447 --> 00:28:55,615
 ILCS.

651
00:28:55,615 --> 00:28:56,883
 IN BONE MARROW TRANSPLANTS,

652
00:28:56,883 --> 00:29:01,454
 THEY ARE NOT LARGELY

653
00:29:01,454 --> 00:29:02,589
 REGENERATED.

654
00:29:02,589 --> 00:29:03,189
 [INDISCERNIBLE]

655
00:29:03,189 --> 00:29:07,093
 >> HE DID LOOK AT THAT IN
THE

656
00:29:07,093 --> 00:29:10,563
 PAPER WITH ALLEN, THIS IS A

657
00:29:10,563 --> 00:29:15,001
 PAPER IN IMMUNOLOGY, ALLEN

658
00:29:15,001 --> 00:29:16,669
 FISCHER COLLABORATION AND THAT

659
00:29:16,669 --> 00:29:19,372
 IS A GREAT QUESTION AND HE

660
00:29:19,372 --> 00:29:20,240
 LOOKED AT THAT.

661
00:29:20,240 --> 00:29:21,808
 THAT LOOKED AT SYSTEMIC

662
00:29:21,808 --> 00:29:23,076
 RESPONSES, THE PATIENTS WERE

663
00:29:23,076 --> 00:29:25,011
 OUT OF THE HOSPITAL BUT STILL

664
00:29:25,011 --> 00:29:26,346
 HAD CLINICAL SYMPTOMS AND

665
00:29:26,346 --> 00:29:30,650
 PROBLEMS, A LOT OF THEM WERE

666
00:29:30,650 --> 00:29:31,217
 ON IBIG FOR INSTANCE.

667
00:29:31,217 --> 00:29:34,420
 AND WE WERE LUCKY ENOUGH TO DO

668
00:29:34,420 --> 00:29:36,356
 NASAL SWABS ON ALL THOSE

669
00:29:36,356 --> 00:29:40,960
 PATIENTS AND STUDIED THEIR

670
00:29:40,960 --> 00:29:42,095
 MUCOSAL RESPONSES, PUBLISHED

671
00:29:42,095 --> 00:29:44,197
 THAT IN A PAPER IN BLOOD THIS

672
00:29:44,197 --> 00:29:46,132
 YEAR SO IF YOU ARE INTERESTED,

673
00:29:46,132 --> 00:29:48,001
 YOU CAN TAKE A LOOK AT THAT.

674
00:29:48,001 --> 00:29:51,604
 ALL THOSE PATIENTS HAVE ILCS

675
00:29:51,604 --> 00:29:53,773
 IN THEIR NOSE.

676
00:29:53,773 --> 00:29:55,375
 THEY ARE NOT NORMAL AND THEY

677
00:29:55,375 --> 00:30:01,814
 HAD SOME ISSUES AND THEY HAVE 

678
00:30:01,814 --> 00:30:05,118
 CARRIAGE OF STRENGTHO --

679
00:30:05,118 --> 00:30:06,286
 STREPTOMONIA THAT IS NOT

680
00:30:06,286 --> 00:30:06,619
 NORMAL.

681
00:30:06,619 --> 00:30:09,455
 SO I THINK WHAT THAT IS

682
00:30:09,455 --> 00:30:13,126
 TELLING US IS THE ILCS ARE

683
00:30:13,126 --> 00:30:14,994
 IMPORTANT FOR THE IGA

684
00:30:14,994 --> 00:30:17,363
 PRODUCTION AND EVERYBODY WHO

685
00:30:17,363 --> 00:30:19,666
 UNDERGOES THOSE TRANSPLANTS SO

686
00:30:19,666 --> 00:30:27,473
 PROBABLY DO IT THROUGH

687
00:30:27,473 --> 00:30:28,808
 INTRAVENOUS GLOBULARITY.

688
00:30:28,808 --> 00:30:29,175
 [APPLAUSE]

689
00:30:29,175 --> 00:30:29,609
 >> THANK YOU.

690
00:30:29,609 --> 00:30:40,186
 IF YOU CAN HEAR ME, OUR NEXT 

691
00:30:45,792 --> 00:30:48,594
 SPEAKER IS AL HE IS FROM

692
00:30:48,594 --> 00:30:54,434
 SINGER WHO WILL TALK ABOUT

693
00:30:54,434 --> 00:30:56,436
 TRANSSCRIPTIONAL DETERMINATION

694
00:30:56,436 --> 00:30:58,237
 OF T LINEAGE FATE.

695
00:30:58,237 --> 00:31:03,109
 >> CAN YOU HEAR ME?

696
00:31:03,109 --> 00:31:04,711
 I AM MIC'D AND NOBODY CAN HEAR

697
00:31:04,711 --> 00:31:05,144
 ME.

698
00:31:05,144 --> 00:31:06,913
 SO THANK YOU FOR COMING TO

699
00:31:06,913 --> 00:31:08,514
 THIS MEETING, THANK YOU FOR

700
00:31:08,514 --> 00:31:12,552
 COMING TO THE SESSION. 

701
00:31:12,552 --> 00:31:21,761
 REALLY ENJOYING IT.

702
00:31:21,761 --> 00:31:31,371
 SO SO THIS IS MY GROUP, THAT

703
00:31:31,371 --> 00:31:41,047
 IS NOT MY BOSS, HE WORKS FOR

704
00:31:41,047 --> 00:31:51,190
 ME, AND I HAVE TO ACKNOWLEDGE

705
00:31:51,190 --> 00:31:51,491
 THEM.

706
00:31:51,491 --> 00:31:58,331
 SO WE ALL KNOW ILCS ARE

707
00:31:58,331 --> 00:32:00,700
 COMPLICATED T CELLS AND I WILL

708
00:32:00,700 --> 00:32:02,769
 CAN TALKING ABOUT K CELLS --

709
00:32:02,769 --> 00:32:03,336
 YOU KNOW WHAT?

710
00:32:03,336 --> 00:32:08,041
 I AM NOT GOING TO DO THIS.

711
00:32:08,041 --> 00:32:10,743
 SO I AM GOING TO BE TALKING

712
00:32:10,743 --> 00:32:13,012
 ABOUT NK CELLS TODAY AND THESE

713
00:32:13,012 --> 00:32:15,982
 ARE THE INNATE COUNTERPART TO

714
00:32:15,982 --> 00:32:22,622
 T CELLS BECAUSE THEY CAN KILL

715
00:32:22,622 --> 00:32:29,062
 IN THE CASE OF LOOKING FOR

716
00:32:29,062 --> 00:32:29,395
 VIRUSES.

717
00:32:29,395 --> 00:32:32,832
 AND ELIMINATE TUMOR CELLS. 

718
00:32:32,832 --> 00:32:39,172
 SO INTERESTING CELLS.

719
00:32:39,172 --> 00:32:46,045
 AND THIS IS THE PATHWAY OF

720
00:32:46,045 --> 00:32:48,548
 EARLY DEVELOPMENT ILCS IN

721
00:32:48,548 --> 00:32:57,256
 ADULT MICE, WE KNOW THEY ARE 

722
00:32:57,256 --> 00:32:58,724
 EARLY NK PRECURSORS.

723
00:32:58,724 --> 00:33:04,263
 WE THINK OF THE IL C1'S, 2'S

724
00:33:04,263 --> 00:33:07,300
 AND 3'S THAT WE THINK OF AS

725
00:33:07,300 --> 00:33:07,967
 HELPER CELLS.

726
00:33:07,967 --> 00:33:11,537
 THE DEVELOPMENT OF NK CELLS IS

727
00:33:11,537 --> 00:33:17,143
 MUCH LESS UNDERSTOOD,

728
00:33:17,143 --> 00:33:19,745
 ESPECIALLY WITH NK CELLS.

729
00:33:19,745 --> 00:33:26,819
 SO I THINK MOST RECENTLY AND

730
00:33:26,819 --> 00:33:30,323
 CLEARLY, THEY HELP ILCS BUT

731
00:33:30,323 --> 00:33:34,594
 HOW DO THEY DEVELOP THESE

732
00:33:34,594 --> 00:33:35,495
 CONSEQUENCES?

733
00:33:35,495 --> 00:33:38,531
 DO THEY MAKE ANOTHER CELL TO

734
00:33:38,531 --> 00:33:40,133
 WORK ON THE CELLS?

735
00:33:40,133 --> 00:33:43,703
 SO THIS IS THE SEQUENCING AND

736
00:33:43,703 --> 00:33:45,972
 WE MAKE A NUMBER OF

737
00:33:45,972 --> 00:33:47,673
 ASSUMPTIONS THAT I DON'T HAVE

738
00:33:47,673 --> 00:33:53,146
 TIME TO GO INTO. 

739
00:33:53,146 --> 00:34:03,723
 BUT MOST OF THESE CELLS ARE NK

740
00:34:04,824 --> 00:34:05,158
 CELLS.

741
00:34:05,158 --> 00:34:13,099
 SO YOU HAVE THE ENKP HERE AND

742
00:34:13,099 --> 00:34:16,202
 OTHER CELLS WE KNEW ABOUT AND

743
00:34:16,202 --> 00:34:17,937
 ONE SMALL GROUP OF CELLS WE

744
00:34:17,937 --> 00:34:28,347
 DIDN'T KNOW ABOUT. 

745
00:34:29,916 --> 00:34:38,524
 THE HIGHLY EXPRESSED ILCCELLS

746
00:34:38,524 --> 00:34:42,361
 WE DIDN'T KNOW ABOUT, THEY

747
00:34:42,361 --> 00:34:45,264
 HAVE OTHER MARKERS AND WE

748
00:34:45,264 --> 00:34:49,435
 IDENTIFIED THEM AND PUT THOSE

749
00:34:49,435 --> 00:34:52,104
 DOWN HERE. 

750
00:34:52,104 --> 00:34:58,044
 THEY HAVE BEEN DESCRIBED WITH

751
00:34:58,044 --> 00:35:00,746
 AVERAGE EXPRESSION, BUT A TINY

752
00:35:00,746 --> 00:35:06,852
 POPULATION HERE, I HAD NOT

753
00:35:06,852 --> 00:35:07,253
 KNOWN THAT.

754
00:35:07,253 --> 00:35:14,427
 SO HERE WE ARE ISOLATING THE

755
00:35:14,427 --> 00:35:16,796
 PROCESS, TRANSFERRING THEM

756
00:35:16,796 --> 00:35:17,930
 INTO MICE AND THE FUNCTION

757
00:35:17,930 --> 00:35:19,765
 THEY HAVE WITH REGARD TO LIVER

758
00:35:19,765 --> 00:35:25,471
 AND THESE CELLS WOULD BE ILCP1

759
00:35:25,471 --> 00:35:30,076
 AND JUST TO CONFIRM WHAT

760
00:35:30,076 --> 00:35:32,378
 PEOPLE KNOW, THEY ALSO MAKE T

761
00:35:32,378 --> 00:35:32,945
 CELLS.

762
00:35:32,945 --> 00:35:43,522
 SO WHEN WE TRANSFER THESE GUYS

763
00:35:46,892 --> 00:35:48,494
 USING ILC CELLS, THEY DON'T

764
00:35:48,494 --> 00:35:51,897
 MAKE ANY T CELLS. 

765
00:35:51,897 --> 00:35:54,734
 SO WE HAVE TWO GROUPS THAT CAN

766
00:35:54,734 --> 00:35:56,269
 MAKE T CELLS AND WE WANT TO

767
00:35:56,269 --> 00:35:57,103
 UNDERSTAND THE RELATIONSHIP

768
00:35:57,103 --> 00:35:57,536
 BETWEEN THEM.

769
00:35:57,536 --> 00:35:59,705
 AND THIS IS A COMPLICATE SLIDE

770
00:35:59,705 --> 00:36:02,775
 SO IF I GET THROUGH THIS, I AM

771
00:36:02,775 --> 00:36:03,909
 DOING WELL, OKAY?

772
00:36:03,909 --> 00:36:09,749
 THE TOP PART, JUST REPEATING

773
00:36:09,749 --> 00:36:11,951
 AN EXPERIMENT THAT ALLEN

774
00:36:11,951 --> 00:36:16,856
 PUBLISHED, IT IS A LITTLE

775
00:36:16,856 --> 00:36:21,727
 COMPLICATED BECAUSE IT IS NOT

776
00:36:21,727 --> 00:36:24,530
 AS LEAKY SO WE HAVE TO

777
00:36:24,530 --> 00:36:25,498
 DEMONSTRATE THE CELLS AND THAT

778
00:36:25,498 --> 00:36:27,800
 IS WHAT WE HAVE DONE.

779
00:36:27,800 --> 00:36:31,871
 NK CELLS HAVE SOME LEVEL OF

780
00:36:31,871 --> 00:36:33,072
 LINEAGE TRACING, IT IS NOT

781
00:36:33,072 --> 00:36:37,476
 ZERO BUT IT IS NOT 20 PERCENT.

782
00:36:37,476 --> 00:36:40,246
 ILC'S ARE HEAVILY TRACED.

783
00:36:40,246 --> 00:36:44,250
 THIS NEW ACTIVITY WE ARE 

784
00:36:44,250 --> 00:36:48,020
 DESCRIBING IS INCREASED BY

785
00:36:48,020 --> 00:36:48,321
 INKP.

786
00:36:48,321 --> 00:36:49,522
 AND DOWNSTREAM, YOU CAN SEE

787
00:36:49,522 --> 00:36:58,230
 THEY ARE STARTING TO EXPRESS

788
00:36:58,230 --> 00:37:00,933
 THE ROSA STOP, IS WHAT THEY

789
00:37:00,933 --> 00:37:03,069
 ARE DOING SO WHAT HE WAS DOING

790
00:37:03,069 --> 00:37:05,971
 WAS TRANSFERRING THIS OUT OF

791
00:37:05,971 --> 00:37:06,572
 THE MICE.

792
00:37:06,572 --> 00:37:08,541
 AND I WILL START OVER HERE.

793
00:37:08,541 --> 00:37:11,477
 IF YOU TRANSFER THEM, THEY

794
00:37:11,477 --> 00:37:12,278
 MAKE ILC'S.

795
00:37:12,278 --> 00:37:15,748
 LOOKING AT THE LIVER HERE AT

796
00:37:15,748 --> 00:37:20,052
 IL C1'S, THESE ARE HEAVILY

797
00:37:20,052 --> 00:37:22,021
 LINEAGE TRACED.

798
00:37:22,021 --> 00:37:28,828
 AND THESE ENKP CELLS ARE 

799
00:37:28,828 --> 00:37:29,995
 HEAVILY LINEAGE TRACED.

800
00:37:29,995 --> 00:37:34,633
 IF WE TRANSFER ENKP CELLS,

801
00:37:34,633 --> 00:37:39,839
 THEY MAKE ILC CELLS AND THEY

802
00:37:39,839 --> 00:37:43,042
 ARE NOT HEAVILY TRACED.

803
00:37:43,042 --> 00:37:53,619
 SO IF WE TRANSFER THE ENKP-NK

804
00:37:54,620 --> 00:37:57,923
 CELLS, THEY ARE VERY HEAVILY

805
00:37:57,923 --> 00:38:01,660
 TRACED. 

806
00:38:01,660 --> 00:38:05,765
 SO ON AVERAGE, 70 PERCENT

807
00:38:05,765 --> 00:38:09,034
 ACROSS THE EXPERIMENT. 

808
00:38:09,034 --> 00:38:14,373
 THESE MAKE NK CELLS THAT ARE

809
00:38:14,373 --> 00:38:15,241
 MARKED BY PLZF.

810
00:38:15,241 --> 00:38:16,876
 MAYBE 10 PERCENT OR LESS.

811
00:38:16,876 --> 00:38:17,710
 IT IS NOT ZERO.

812
00:38:17,710 --> 00:38:20,312
 AND YOU MIX THESE TWO, YOU GET

813
00:38:20,312 --> 00:38:22,314
 WHAT PEOPLE NORMALLY SEE WHICH

814
00:38:22,314 --> 00:38:24,850
 IS 20 PERCENT ON AVERAGE

815
00:38:24,850 --> 00:38:25,918
 LINEAGE TRACING AND IF YOU

816
00:38:25,918 --> 00:38:28,154
 LOOK AT THAT, YOU CAN MAP IT

817
00:38:28,154 --> 00:38:31,891
 AND YOU CAN CONCLUDE FROM JUST

818
00:38:31,891 --> 00:38:34,160
 THOSE NUMBERS, IT -- IF YOU DO

819
00:38:34,160 --> 00:38:35,294
 THE MATH THAT 80 PERCENT ARE

820
00:38:35,294 --> 00:38:36,462
 COMING FROM THIS NEW CELL THAT

821
00:38:36,462 --> 00:38:39,598
 I TOLD YOU ABOUT AND ACTUALLY

822
00:38:39,598 --> 00:38:43,035
 A SMALLER FRACTION BUT A

823
00:38:43,035 --> 00:38:43,836
 SUBSTANTIAL FRACTION,

824
00:38:43,836 --> 00:38:45,404
 20 PERCENT OR MAYBE A LITTLE

825
00:38:45,404 --> 00:38:48,374
 LESS ARE ACTUALLY COMING FROM

826
00:38:48,374 --> 00:38:49,442
 ILC'S.

827
00:38:49,442 --> 00:38:54,814
 SO TWO PATHWAYS. 

828
00:38:54,814 --> 00:38:56,382
 OKAY, ARE THESE DIFFERENT

829
00:38:56,382 --> 00:38:58,150
 CELLS OR THE SAME CELLS?

830
00:38:58,150 --> 00:39:00,119
 SO WE SORT THEM OUT AND PUT

831
00:39:00,119 --> 00:39:02,288
 THEM IN MICE AND LOOK AT

832
00:39:02,288 --> 00:39:02,688
 THOSE.

833
00:39:02,688 --> 00:39:12,064
 AND IN THIS CASE THE 

834
00:39:12,064 --> 00:39:16,502
 SEQUENCING, ALL CONTROLLED 

835
00:39:16,502 --> 00:39:18,537
 TOGETHER AND THE SHORT ANSWER

836
00:39:18,537 --> 00:39:21,207
 IS THEY ARE NOT

837
00:39:21,207 --> 00:39:21,841
 TRANSCRIPTIONAL CELLS.

838
00:39:21,841 --> 00:39:24,310
 BUT IF YOU LOOK AT THE NK

839
00:39:24,310 --> 00:39:26,078
 CELLS, THESE ARE THE GENES

840
00:39:26,078 --> 00:39:27,112
 THEY HIGHLY EXPRESS.

841
00:39:27,112 --> 00:39:28,814
 SO THESE ARE THE TRANSCRIPTION

842
00:39:28,814 --> 00:39:33,719
 FACTORS I AM SHOWING YOU IN

843
00:39:33,719 --> 00:39:36,522
 DEVELOPMENT AND THEN A BUNCH

844
00:39:36,522 --> 00:39:38,257
 OF GENES ACTIVATING THE

845
00:39:38,257 --> 00:39:41,927
 RECEPTORS. 

846
00:39:41,927 --> 00:39:49,835
 IF YOU LOOK AT THESE ILCP'S,

847
00:39:49,835 --> 00:39:52,204
 THEY ENGAGE OTHER

848
00:39:52,204 --> 00:39:52,805
 TRANSCRIPTION FACTORS.

849
00:39:52,805 --> 00:40:02,882
 THIS IS THE ZEB2 AND THEY

850
00:40:02,882 --> 00:40:03,816
 EXPRESS OTHER MODELS.

851
00:40:03,816 --> 00:40:06,318
 YOU KNOW ONE OF THESE SCALES,

852
00:40:06,318 --> 00:40:08,187
 I WANT TO TALK ABOUT THAT NOW,

853
00:40:08,187 --> 00:40:11,023
 THIS IS THE MOST DIFFERENTLY

854
00:40:11,023 --> 00:40:12,091
 EXPRESSED GENE BETWEEN THESE

855
00:40:12,091 --> 00:40:15,561
 TWO AND I AM SHOWING YOU THAT

856
00:40:15,561 --> 00:40:15,995
 HERE.

857
00:40:15,995 --> 00:40:18,430
 SO THE TWO OF THEM, WHAT THEY

858
00:40:18,430 --> 00:40:19,899
 DID WAS PRETTY MUCH SOMETHING

859
00:40:19,899 --> 00:40:22,468
 IN THE MIDDLE SO IT IS A

860
00:40:22,468 --> 00:40:24,203
 MIXTURE OF NK CELLS.

861
00:40:24,203 --> 00:40:29,308
 SO IF YOU LOOK AT THIS, IT IS

862
00:40:29,308 --> 00:40:32,044
 EXPRESSED BY THESE GUYS AND

863
00:40:32,044 --> 00:40:33,479
 BARELY BY THESE GUYS.

864
00:40:33,479 --> 00:40:38,217
 SO I AM NOT TALKING ABOUT I

865
00:40:38,217 --> 00:40:39,618
 C1'S OR SOMETHING, THESE ARE

866
00:40:39,618 --> 00:40:49,828
 NK CELLS AND ALL EXPRESSED IN

867
00:40:49,828 --> 00:40:51,497
 WAYS THAT PEOPLE CONSIDER IN

868
00:40:51,497 --> 00:40:53,532
 THE MOUSE.

869
00:40:53,532 --> 00:41:00,639
 SO THESE CELLS ARE EXPRESSED 

870
00:41:00,639 --> 00:41:08,981
 IN THE RECEPTOR OF -- MYMV.

871
00:41:08,981 --> 00:41:14,253
 AND IF YOU GET THIS, IT IS

872
00:41:14,253 --> 00:41:18,857
 HUGELY EXPRESSED AND THE ONE

873
00:41:18,857 --> 00:41:21,226
 EXPRESSED HERE ARE THE BULK OF

874
00:41:21,226 --> 00:41:22,461
 THE EXPRESSION.

875
00:41:22,461 --> 00:41:25,831
 AND THIS IS IMPORTANT BECAUSE

876
00:41:25,831 --> 00:41:30,936
 IF YOU USE THE ANTIBODIES, THE

877
00:41:30,936 --> 00:41:31,770
 MICE DIE.

878
00:41:31,770 --> 00:41:35,841
 SO MICE NEED THIS TO SURVIVE,

879
00:41:35,841 --> 00:41:36,342
 MOUSE CMV.

880
00:41:36,342 --> 00:41:38,544
 SO OF COURSE THIS WAS AN

881
00:41:38,544 --> 00:41:40,012
 OPTION BETWEEN THESE TWO

882
00:41:40,012 --> 00:41:43,182
 GROUPS OF NK CELLS, ARE THEY

883
00:41:43,182 --> 00:41:44,917
 FUNCTIONALLY DISTINCT, CAN WE

884
00:41:44,917 --> 00:41:45,284
 SHOW THAT.

885
00:41:45,284 --> 00:41:46,785
 AND WHAT WE ARE DOING NOW IS

886
00:41:46,785 --> 00:41:49,655
 JUST GOING BACK AND CHECKING

887
00:41:49,655 --> 00:41:53,792
 AND WHEN YOU CROSS THEM, THEY

888
00:41:53,792 --> 00:41:56,862
 ABSOLUTELY DO EXPRESS THE

889
00:41:56,862 --> 00:41:57,529
 LINEAGE.

890
00:41:57,529 --> 00:42:00,599
 THE ONES COMING FROM ILCS,

891
00:42:00,599 --> 00:42:02,368
 VERY LITTLE AND AGAIN THIS IS

892
00:42:02,368 --> 00:42:06,572
 WHAT YOU SEE IN THE MOUSE, YOU

893
00:42:06,572 --> 00:42:12,878
 END UP GETTING SOMETHING LIKE

894
00:42:12,878 --> 00:42:14,780
 THAT.

895
00:42:14,780 --> 00:42:18,751
 BUT NOW WITH SIMON'S HELP,

896
00:42:18,751 --> 00:42:24,289
 PICKING UP MICE, WAITING FIVE

897
00:42:24,289 --> 00:42:28,227
 WEEKS, COME BACK AND LOOK AT

898
00:42:28,227 --> 00:42:28,861
 ILC3'S.

899
00:42:28,861 --> 00:42:39,371
 SO THESE WOULD BE THE ENKP

900
00:42:45,544 --> 00:42:46,111
 DERIVED CELLS.

901
00:42:46,111 --> 00:42:48,547
 BUT IF YOU LOOK AT THE MOUSE,

902
00:42:48,547 --> 00:42:52,284
 THIS IS VERY DIFFERENT THAN

903
00:42:52,284 --> 00:42:54,687
 WHAT HAPPENED BECAUSE THESE

904
00:42:54,687 --> 00:42:57,389
 ARE BEING EXPRESSED

905
00:42:57,389 --> 00:42:58,157
 ENORMOUSLY.

906
00:42:58,157 --> 00:43:01,293
 NORMALLY MICE WE DON'T GIVE

907
00:43:01,293 --> 00:43:03,729
 CMV TO, EVEN ON A PER CELL

908
00:43:03,729 --> 00:43:05,698
 BASIS, MAKE THREE OR FOUR

909
00:43:05,698 --> 00:43:08,267
 TIMES AS MANY NK CELLS BUT

910
00:43:08,267 --> 00:43:10,035
 THEY ONLY RECOVER A FEW

911
00:43:10,035 --> 00:43:13,272
 THOUSAND CELLS FROM THIS.

912
00:43:13,272 --> 00:43:16,942
 IN MICE GIVEN MCMV, IT IS

913
00:43:16,942 --> 00:43:19,445
 MILLIONS OF CELLS, SEVERAL

914
00:43:19,445 --> 00:43:20,612
 HUNDRED FOLD EXPANSION.

915
00:43:20,612 --> 00:43:22,748
 BUT ONLY IN THOSE MICE BUT

916
00:43:22,748 --> 00:43:26,518
 NOTHING HAPPENS IN THE MICE

917
00:43:26,518 --> 00:43:31,156
 WHOSE NK CELLS WERE NOT

918
00:43:31,156 --> 00:43:31,790
 EXPRESSED.

919
00:43:31,790 --> 00:43:36,995
 SO NK CELLS ARE KNOWN TO BE

920
00:43:36,995 --> 00:43:38,931
 HETEROGENEOUS AND IT IS NOT

921
00:43:38,931 --> 00:43:42,167
 JUST IN ACTIVATION STATES, IT

922
00:43:42,167 --> 00:43:43,035
 IS DEVELOPMENTALLY.

923
00:43:43,035 --> 00:43:44,803
 THERE IS TWO STATES AND THEY

924
00:43:44,803 --> 00:43:51,210
 AREN'T THE SAME CELLS AND

925
00:43:51,210 --> 00:43:53,545
 REALLY THE COMING FROM THE NEW

926
00:43:53,545 --> 00:43:55,781
 SET I SHOWED YOU, PEOPLE DON'T

927
00:43:55,781 --> 00:43:59,518
 THINK OF THESE AS NK CELLS BUT

928
00:43:59,518 --> 00:44:01,386
 THEY MAKE A DIFFERENT CELL AND

929
00:44:01,386 --> 00:44:03,589
 IT IS UNKNOWN WHAT THEIR

930
00:44:03,589 --> 00:44:05,657
 FUNCTIONS MIGHT BE.

931
00:44:05,657 --> 00:44:09,128
 IT IS SOMETHING WE HAVE YET TO

932
00:44:09,128 --> 00:44:09,528
 UNDERSTAND.

933
00:44:09,528 --> 00:44:12,064
 SO NOW I WANT TO ADDRESS HUMAN

934
00:44:12,064 --> 00:44:16,735
 POPULATIONS THAT ARE VERY

935
00:44:16,735 --> 00:44:18,237
 HETEROGENEOUS AND ONE COMMON

936
00:44:18,237 --> 00:44:22,274
 WAY OF LOOKING AT IT IS TO

937
00:44:22,274 --> 00:44:25,110
 LOOK IN RELATION TO SMALLER

938
00:44:25,110 --> 00:44:26,145
 MARKERS.

939
00:44:26,145 --> 00:44:30,015
 AND THE HUMAN NK SUBSETS IN A

940
00:44:30,015 --> 00:44:32,317
 MAJOR POPULATION SHOW THE NK

941
00:44:32,317 --> 00:44:32,684
 CELLS.

942
00:44:32,684 --> 00:44:33,819
 YOU HAVE THIS MINOR POPULATION

943
00:44:33,819 --> 00:44:36,922
 AND THEN THE LARGER POPULATION

944
00:44:36,922 --> 00:44:39,525
 OF CD16 CELLS AND THESE ARE

945
00:44:39,525 --> 00:44:44,696
 THE CELLS THAT RESPOND TO CMV

946
00:44:44,696 --> 00:44:46,632
 AND PEOPLE GIVEN CMV OR WITH

947
00:44:46,632 --> 00:44:49,001
 THE HISTORY OF CMV HAVE THE

948
00:44:49,001 --> 00:44:50,636
 PRESERVATION OF OTHER MARKERS

949
00:44:50,636 --> 00:44:54,506
 ON THE CELLS INCLUDING CD56.

950
00:44:54,506 --> 00:44:57,509
 SO WHAT WE DID IS WE PULLED A

951
00:44:57,509 --> 00:45:01,113
 BUNCH OF SINGLE CELL DATA FROM

952
00:45:01,113 --> 00:45:06,118
 OTHER PEOPLE, THESE DATA HERE,

953
00:45:06,118 --> 00:45:11,990
 AND BECAUSE THEY ARE 

954
00:45:11,990 --> 00:45:19,498
 SITE-SEQ'D HERE, THESE ARE

955
00:45:19,498 --> 00:45:24,469
 CD56 AND 57 AND WE TAKE THESE

956
00:45:24,469 --> 00:45:26,772
 EXPRESSED GENES AND APPLY THEM

957
00:45:26,772 --> 00:45:29,241
 TO GENERATE A TRANSCRIPTIONAL

958
00:45:29,241 --> 00:45:31,210
 SCORE ACROSS THESE CLUSTERS,

959
00:45:31,210 --> 00:45:34,213
 WHAT YOU SEE IS THESE TWO

960
00:45:34,213 --> 00:45:36,415
 CLUSTERS HIGH LIE EXPRESS THE

961
00:45:36,415 --> 00:45:42,721
 GENES THAT ARE CHARACTERISTIC

962
00:45:42,721 --> 00:45:44,623
 OF THE ENK CELLS.

963
00:45:44,623 --> 00:45:46,158
 AND CONVERSELY IF YOU LOOK AT

964
00:45:46,158 --> 00:45:48,227
 THE GENES THAT ARE HIGH LIE

965
00:45:48,227 --> 00:45:51,129
 EXPRESSED IN THE ILC CELLS,

966
00:45:51,129 --> 00:45:54,600
 THOSE ARE HIGHLY EXPRESSED IN

967
00:45:54,600 --> 00:45:58,604
 THE 56 CELLS BUT NOT THE 57.

968
00:45:58,604 --> 00:46:00,138
 SO THAT IS ALL THE TIME I

969
00:46:00,138 --> 00:46:00,672
 HAVE.

970
00:46:00,672 --> 00:46:03,141
 WHAT I HAVE SHOWN YOU IS THAT

971
00:46:03,141 --> 00:46:11,383
 NK CELLS ARE HETEROGENEOUS BUT

972
00:46:11,383 --> 00:46:14,920
 NOT TRANSCRIPTOMIC, THIS MAKES

973
00:46:14,920 --> 00:46:20,092
 THE BULK OF CELLS AND GENERATE

974
00:46:20,092 --> 00:46:24,863
 A SMALLER POPULATION OF

975
00:46:24,863 --> 00:46:25,898
 UNCONVENTIONAL NK CELLS THAT

976
00:46:25,898 --> 00:46:29,067
 WE DON'T YET UNDERSTAND AND

977
00:46:29,067 --> 00:46:31,303
 THE PATHWAYS MAY BE CONSERVED

978
00:46:31,303 --> 00:46:36,575
 IN HUMANS. 

979
00:46:36,575 --> 00:46:39,077
 THANK YOU.

980
00:46:39,077 --> 00:46:40,479
 [APPLAUSE]

981
00:46:40,479 --> 00:46:41,780
 [ OFF MIC ]

982
00:46:41,780 --> 00:46:45,484
 >> WELL, IT IS
IMMUNODEFICIENT

983
00:46:45,484 --> 00:46:47,152
 MICE.

984
00:46:47,152 --> 00:46:48,954
 THE NK IS FROM EFFICIENT MICE

985
00:46:48,954 --> 00:46:53,225
 BUT YOU SEE THE SAME

986
00:46:53,225 --> 00:46:54,026
 TRANSCRIPTIONAL PROFILES IF

987
00:46:54,026 --> 00:46:55,861
 YOU LOOK FOR THOSE SETS OF

988
00:46:55,861 --> 00:46:59,164
 GENES I SHARED WITH YOU THAT

989
00:46:59,164 --> 00:47:01,166
 ARE DIFFERENTIALLY EXPRESSED

990
00:47:01,166 --> 00:47:02,334
 YOU GET 80 PERCENT THAT

991
00:47:02,334 --> 00:47:05,304
 EXPRESS ONE SET OF GENES AND

992
00:47:05,304 --> 00:47:07,806
 20 PERCENT THAT EXPRESS THE

993
00:47:07,806 --> 00:47:12,878
 OTHER GENES.

994
00:47:12,878 --> 00:47:14,513
 [ OFF MIC ]

995
00:47:14,513 --> 00:47:19,952
 >> NO, NO, AND THEY --
OH, I

996
00:47:19,952 --> 00:47:21,353
 AM SORRY, YOU WANT TO --

997
00:47:21,353 --> 00:47:25,524
 >> MY QUESTION WAS WITH
THE

998
00:47:25,524 --> 00:47:26,959
 GENE EXPRESSION YOU SHOWED

999
00:47:26,959 --> 00:47:31,163
 WITH NK COMING FROM THE ILC'S,

1000
00:47:31,163 --> 00:47:33,031
 WHETHER THAT WAS IN TISSUE

1001
00:47:33,031 --> 00:47:36,802
 VERY CLEAN AND IT WOULD BE

1002
00:47:36,802 --> 00:47:40,105
 DIFFERENT IF WE WERE THINKING

1003
00:47:40,105 --> 00:47:45,911
 ABOUT TUMORS BECAUSE NK CELLS

1004
00:47:45,911 --> 00:47:47,713
 ARE EXPRESSED DIFFERENTLY IN

1005
00:47:47,713 --> 00:47:48,213
 TUMORS.

1006
00:47:48,213 --> 00:47:50,048
 >> SO YOU HAVE STARTED TO
LOOK

1007
00:47:50,048 --> 00:47:54,386
 AT THAT? 

1008
00:47:54,386 --> 00:47:54,753
 >> YES.

1009
00:47:54,753 --> 00:47:55,220
 >> ABSOLUTELY.

1010
00:47:55,220 --> 00:48:00,492
 SO WE HAVE LOOKED AT THE NK

1011
00:48:00,492 --> 00:48:02,594
 CELLS, CD56 AND SEEN MORE OF

1012
00:48:02,594 --> 00:48:04,563
 THOSE IN MICE SO THEY SEEM TO

1013
00:48:04,563 --> 00:48:06,932
 BE DOING SIMILAR THINGS IN

1014
00:48:06,932 --> 00:48:07,499
 OTHER TISSUES.

1015
00:48:07,499 --> 00:48:10,769
 >> THANK YOU FOR YOUR
TALK.

1016
00:48:10,769 --> 00:48:12,971
 WHAT FACTOR OR EFFECT DO YOU

1017
00:48:12,971 --> 00:48:16,341
 BELIEVE IS CAUSING THE SPLIT

1018
00:48:16,341 --> 00:48:21,913
 OF ILC'S IN PRO GENUINE 

1019
00:48:21,913 --> 00:48:22,914
 TORES -- PROGENITORS --

1020
00:48:22,914 --> 00:48:25,283
 >> I WOULD LIKE TO
ADDRESS

1021
00:48:25,283 --> 00:48:25,751
 THAT.

1022
00:48:25,751 --> 00:48:27,919
 SO WE HAVE BEEN DOING THE WORK

1023
00:48:27,919 --> 00:48:35,761
 THAT SHOW THESE ARE SIGNAL

1024
00:48:35,761 --> 00:48:36,628
 TRANSCRIPTIONAL FACTORS BUT I

1025
00:48:36,628 --> 00:48:39,765
 DON'T KNOW THAT FOR SURE.

1026
00:48:39,765 --> 00:48:43,168
 >> THANKS FOR THE TALK,
VERY

1027
00:48:43,168 --> 00:48:44,770
 NICE.

1028
00:48:44,770 --> 00:48:46,438
 SO THE MCMV INFECTION, DID YOU

1029
00:48:46,438 --> 00:48:48,373
 LOOK IN THE LIVER?

1030
00:48:48,373 --> 00:48:49,975
 BECAUSE THE SPLEEN IS ONE AREA

1031
00:48:49,975 --> 00:48:52,444
 YOU START TO SEE THIS BUT

1032
00:48:52,444 --> 00:48:55,747
 THERE IS A LOT MORE GOING ON

1033
00:48:55,747 --> 00:48:58,250
 IN THE LIVER BECAUSE THINGS

1034
00:48:58,250 --> 00:49:00,252
 TEND TO BE MORE RICH THERE AND

1035
00:49:00,252 --> 00:49:01,720
 SO I AM WONDERING IF YOU

1036
00:49:01,720 --> 00:49:03,221
 LOOKED IN THE LIVER.

1037
00:49:03,221 --> 00:49:05,323
 >> SO WE LOOKED AT LIVER
AND

1038
00:49:05,323 --> 00:49:07,793
 SKIN BOTH AND WHAT I SHOWED

1039
00:49:07,793 --> 00:49:12,898
 YOU IS TRUE IN BOTH SITES.

1040
00:49:12,898 --> 00:49:18,003
 THEY ARE NOT RESPONDING TO

1041
00:49:18,003 --> 00:49:19,237
 CMV.

1042
00:49:19,237 --> 00:49:19,938
 >> REMARKABLE THE

1043
00:49:19,938 --> 00:49:23,575
 UNCONVENTIONAL ONES ARE REALLY

1044
00:49:23,575 --> 00:49:25,143
 LACKING THE IL49'S AND IT

1045
00:49:25,143 --> 00:49:27,712
 MAKES THEY THINK ABOUT THE

1046
00:49:27,712 --> 00:49:29,314
 SCRIPT FROM KUMAR WHO WOULD

1047
00:49:29,314 --> 00:49:31,983
 PUT THEM IN VITRO AND EXPAND

1048
00:49:31,983 --> 00:49:34,686
 THEM WITH IL13 AND BASICALLY

1049
00:49:34,686 --> 00:49:42,427
 YOU GET THESE CYTOTOXIC NK

1050
00:49:42,427 --> 00:49:48,233
 CELLS BUT NEVER DEVELOPED INTO

1051
00:49:48,233 --> 00:49:53,171
 IL9'S SO I WONDER IF THE

1052
00:49:53,171 --> 00:49:57,809
 PATHWAY IS PROHIBITING THEM

1053
00:49:57,809 --> 00:49:58,910
 FROM --

1054
00:49:58,910 --> 00:49:59,377
 [INDISCERNIBLE]

1055
00:49:59,377 --> 00:50:01,246
 >> SO WE GENERATE NK

1056
00:50:01,246 --> 00:50:07,719
 POPULATIONS IN VITRO BUT WE

1057
00:50:07,719 --> 00:50:16,161
 DON'T SEE THE CYTODYNAMIC

1058
00:50:16,161 --> 00:50:17,596
 POPULATIONS SO WE THINK THAT

1059
00:50:17,596 --> 00:50:21,900
 MIGHT BE A LATE MATURATION

1060
00:50:21,900 --> 00:50:22,367
 EVENT.

1061
00:50:22,367 --> 00:50:26,805
 THANK YOU, IT IS GOOD TO KNOW

1062
00:50:26,805 --> 00:50:29,608
 ABOUT THIS EXPERIMENT.

1063
00:50:29,608 --> 00:50:30,442
 THANK YOU.

1064
00:50:30,442 --> 00:50:31,076
 [APPLAUSE]

1065
00:50:31,076 --> 00:50:32,210
 >> MY GREAT PLEASURE TO

1066
00:50:32,210 --> 00:50:42,654
 INTRODUCE A FRIEND AND

1067
00:50:57,702 --> 00:51:01,273
 COLLEAGUE SHAWN PARK AND

1068
00:51:01,273 --> 00:51:02,541
 STUDYING ILC CELLS.

1069
00:51:02,541 --> 00:51:04,342
 >> GOOD MORNING, MY NAME
IS

1070
00:51:04,342 --> 00:51:05,644
 SHAWN PARK AND TODAY I AM

1071
00:51:05,644 --> 00:51:08,079
 GOING TO SHARE WITH YOU DATA

1072
00:51:08,079 --> 00:51:11,149
 ON THE INNATE POPULATION OF NK

1073
00:51:11,149 --> 00:51:12,217
 CELLS.

1074
00:51:12,217 --> 00:51:22,694
 SO AS YOU KNOW, THEY ARE

1075
00:51:42,280 --> 00:51:45,150
 INVARIANT NKT CELLS, THEY ARE

1076
00:51:45,150 --> 00:51:48,954
 LINEAGE CELLS, SELECTED BY

1077
00:51:48,954 --> 00:51:53,858
 NONCLASSICAL MHC-1 AND REWRACK

1078
00:51:53,858 --> 00:51:57,596
 TO GLYCO LIPIDS, NOT PEPTIDES.

1079
00:51:57,596 --> 00:52:08,106
 SO THE INVARIANT CELLS ARE

1080
00:52:10,508 --> 00:52:12,377
 VARIABLE AND THIS RAISES THE

1081
00:52:12,377 --> 00:52:13,511
 QUESTION OF HOW THEY ARE

1082
00:52:13,511 --> 00:52:15,680
 RELATED TO T CELLS.

1083
00:52:15,680 --> 00:52:18,383
 SO HERE YOU SEE THE VARIABLE

1084
00:52:18,383 --> 00:52:22,954
 CHAIN WHERE THE T CELL IS

1085
00:52:22,954 --> 00:52:27,626
 EXPRESSING MHC AND YOU SEE THE

1086
00:52:27,626 --> 00:52:31,096
 MAJORITY OF CELLS ARE COMING

1087
00:52:31,096 --> 00:52:33,932
 FROM THE MHC AND IN THE DATA

1088
00:52:33,932 --> 00:52:38,637
 BINDS TO THE GLYCOLIPID FOR

1089
00:52:38,637 --> 00:52:41,673
 THE SIGNALING. 

1090
00:52:41,673 --> 00:52:52,183
 AND THE VITAL LIKE IN COLIPID 

1091
00:52:52,183 --> 00:52:56,688
 -- GLYCO LIPIDS AND THIS

1092
00:52:56,688 --> 00:52:59,891
 STIMULATES NKT CELLS OVER HERE

1093
00:52:59,891 --> 00:53:06,064
 AND SHOWS A STRONGER

1094
00:53:06,064 --> 00:53:14,339
 ACTIVATION OF THE MHC65 AND

1095
00:53:14,339 --> 00:53:15,173
 69.

1096
00:53:15,173 --> 00:53:22,814
 SO YOU CAN USE THIS TO LOOK AT

1097
00:53:22,814 --> 00:53:24,249
 THE INNATE T CELLS AND YOU CAN

1098
00:53:24,249 --> 00:53:31,556
 SEE THESE IN A NORMAL MOUSE 

1099
00:53:31,556 --> 00:53:35,460
 WITH THE ILC CELLS AND MORE

1100
00:53:35,460 --> 00:53:36,695
 IMPORTANTLY, THE NKT CELLS

1101
00:53:36,695 --> 00:53:40,198
 DOING ALL THE WORK WITH THE

1102
00:53:40,198 --> 00:53:48,640
 MOLECULAR, IF YOU LOOK AT THE

1103
00:53:48,640 --> 00:53:51,676
 TRANSCRIPT ALONE, IT IS MAKING

1104
00:53:51,676 --> 00:53:52,277
 NKT CELLS.

1105
00:53:52,277 --> 00:53:55,880
 SO IN THE MOUSE, YOU CAN SEE

1106
00:53:55,880 --> 00:53:58,750
 10 TO 24 INCREASE IN T CELLS

1107
00:53:58,750 --> 00:54:00,852
 SO THE NKT CELLS IS A GOOD

1108
00:54:00,852 --> 00:54:02,754
 MODEL FOR THE STUDIES AND WHAT

1109
00:54:02,754 --> 00:54:05,924
 WE WANT TO UNDERSTAND

1110
00:54:05,924 --> 00:54:07,992
 INITIALLY IS THE MOUSE LINK

1111
00:54:07,992 --> 00:54:08,893
 WITH GENERAL ACTIVITIES AND

1112
00:54:08,893 --> 00:54:11,129
 THIS IS THE EXPERIMENT WE DID

1113
00:54:11,129 --> 00:54:13,498
 INITIALLY. 

1114
00:54:13,498 --> 00:54:17,135
 SO WE TAKE THE MOUSE AND

1115
00:54:17,135 --> 00:54:23,641
 INJECT INTO THE NKT CELLS AND

1116
00:54:23,641 --> 00:54:25,310
 THEN WITH THE EXPERIMENT LOOK

1117
00:54:25,310 --> 00:54:27,112
 AT THE NKT CELLS SO HERE IS

1118
00:54:27,112 --> 00:54:30,081
 WHAT IT LOOKS LIKE.

1119
00:54:30,081 --> 00:54:31,816
 YOU SEE THE CELLS IN THE

1120
00:54:31,816 --> 00:54:37,021
 SPLEEN AND WITH NKT CELLS, YOU

1121
00:54:37,021 --> 00:54:44,796
 CAN SEE WITH BINDING AND

1122
00:54:44,796 --> 00:54:45,597
 ACTIVATION HERE GENERATES

1123
00:54:45,597 --> 00:54:47,298
 PRETTY MUCH THE SAME BUT WHAT

1124
00:54:47,298 --> 00:54:49,501
 WE KNOW IS THEY ARE HIGHLY

1125
00:54:49,501 --> 00:54:53,271
 ACTIVATED WHEN YOU EXPRESS A

1126
00:54:53,271 --> 00:55:00,478
 HIGH AMOUNT OF CELLS YOU GET T

1127
00:55:00,478 --> 00:55:01,880
 CELLS BUT DON'T REALLY EXPAND.

1128
00:55:01,880 --> 00:55:04,716
 SO YOU THINK MAYBE THERE IS

1129
00:55:04,716 --> 00:55:07,485
 SOMETHING MISSING IN VIVO

1130
00:55:07,485 --> 00:55:10,488
 WHERE YOU CAN ACTIVATE THE NKT

1131
00:55:10,488 --> 00:55:13,024
 CELLS BUT DON'T DRIVE TO

1132
00:55:13,024 --> 00:55:14,325
 PROLIFERATION SO MAYBE THERE

1133
00:55:14,325 --> 00:55:16,828
 IS NOT ENOUGH NKT CELLS HERE

1134
00:55:16,828 --> 00:55:19,164
 OR MAYBE THIS IS MISSING A

1135
00:55:19,164 --> 00:55:21,433
 SIGNAL, A SECOND SIGNAL THAT

1136
00:55:21,433 --> 00:55:24,869
 CAN ACTUALLY DRIVE THEM TO

1137
00:55:24,869 --> 00:55:25,470
 PROLIFERATION.

1138
00:55:25,470 --> 00:55:30,842
 AND THE IDEA WE HAD, THE

1139
00:55:30,842 --> 00:55:34,846
 GALCER SIGNAL THAT CAN DRIVE

1140
00:55:34,846 --> 00:55:43,321
 THEM TO T CELLS, THE NKT CELLS

1141
00:55:43,321 --> 00:55:48,793
 TO ACTIVATION WITH

1142
00:55:48,793 --> 00:55:50,929
 COSTIMULATION.

1143
00:55:50,929 --> 00:55:56,100
 SO WHAT EVERYBODY THINKS, IS

1144
00:55:56,100 --> 00:55:57,302
 THERE COSTIMULATORY MOLECULE

1145
00:55:57,302 --> 00:55:59,637
 FOR NKT CELLS AND IS

1146
00:55:59,637 --> 00:56:00,839
 COSTIMULATION REQUIRED FOR

1147
00:56:00,839 --> 00:56:03,441
 FULL ACTIVATION OF EXPANSION

1148
00:56:03,441 --> 00:56:06,911
 OF NKT CELLS?

1149
00:56:06,911 --> 00:56:12,684
 SO WE COMBINE THE T CELLS IN

1150
00:56:12,684 --> 00:56:15,620
 CD28 AND SEE IF IT GETS

1151
00:56:15,620 --> 00:56:17,155
 ACTIVATED AND CAN EXPAND AND

1152
00:56:17,155 --> 00:56:21,559
 THE RESULTS WERE PRETTY

1153
00:56:21,559 --> 00:56:25,997
 DISAPPOINTING COMPARED TO

1154
00:56:25,997 --> 00:56:27,265
 ALONE, THE ANTI-CD28 DIDN'T

1155
00:56:27,265 --> 00:56:28,933
 REALLY WORK OUT VERY WELL.

1156
00:56:28,933 --> 00:56:32,270
 SO CONSISTENT WITH THE

1157
00:56:32,270 --> 00:56:34,272
 LITERATURE ALSO DOESN'T REALLY

1158
00:56:34,272 --> 00:56:38,977
 DO A LOT, THE CD28 WITH ENK

1159
00:56:38,977 --> 00:56:39,344
 CELLS.

1160
00:56:39,344 --> 00:56:48,553
 SO WHEN YOU ARE LOOKING AT VA

1161
00:56:48,553 --> 00:56:53,291
 14, IT DIDN'T REALLY EXPRESS

1162
00:56:53,291 --> 00:56:54,125
 THAT.

1163
00:56:54,125 --> 00:56:55,793
 SO WE PUBLISHED A PAPER

1164
00:56:55,793 --> 00:57:01,966
 EARLIER THIS YEAR AND WHAT WE

1165
00:57:01,966 --> 00:57:12,544
 FOUND IS THE VL3 -- DR3, WHAT

1166
00:57:14,245 --> 00:57:19,484
 WE FOUND IS THEY PRODUCEDDR3

1167
00:57:19,484 --> 00:57:27,659
 AND LIVE DR3 LEADS TO 

1168
00:57:27,659 --> 00:57:28,059
 ACTIVATION.

1169
00:57:28,059 --> 00:57:30,061
 SO LO AND BE HOLD WHAT THEY

1170
00:57:30,061 --> 00:57:34,065
 FOUND IN THE T CELLS IS DR3 IS

1171
00:57:34,065 --> 00:57:34,999
 EXPRESSED IN ALL T CELLS.

1172
00:57:34,999 --> 00:57:41,773
 SO WHAT IS DR3? 

1173
00:57:41,773 --> 00:57:48,046
 IT IS CALLED DEFENDANT 

1174
00:57:48,046 --> 00:57:52,317
 RECEPTOR, A PRIMER, IT IS A

1175
00:57:52,317 --> 00:57:56,588
 TNF RECEPTOR IN THE SUPER

1176
00:57:56,588 --> 00:57:59,090
 CYTOKINE FAMILY AND CAN

1177
00:57:59,090 --> 00:58:03,494
 TRIGGER LIKE ANY MOLECULE

1178
00:58:03,494 --> 00:58:05,296
 INTERACTION.

1179
00:58:05,296 --> 00:58:06,197
 T L1A IS CLEAN.

1180
00:58:06,197 --> 00:58:09,734
 AND IN THE MOUSE MODEL, THERE

1181
00:58:09,734 --> 00:58:12,904
 IS A DR3 ANTIBODY SO WHAT WE

1182
00:58:12,904 --> 00:58:16,240
 DID WAS SAY OKAY LET'S TEST

1183
00:58:16,240 --> 00:58:18,643
 THIS IF DR3 CAN DO SIGNALING

1184
00:58:18,643 --> 00:58:19,677
 THROUGH ACTIVATION AND

1185
00:58:19,677 --> 00:58:20,812
 EXPANSION.

1186
00:58:20,812 --> 00:58:25,717
 SO THE IDEA IS LET'S INJECT

1187
00:58:25,717 --> 00:58:27,218
 THIS WITH ANTI-DR3 AND SEE IF

1188
00:58:27,218 --> 00:58:31,122
 WE CAN GET A EXPANSION OF NKT

1189
00:58:31,122 --> 00:58:31,656
 CELLS.

1190
00:58:31,656 --> 00:58:33,057
 AND I REMEMBER COMING TO THE

1191
00:58:33,057 --> 00:58:35,360
 LAB AND SAYING THERE IS A

1192
00:58:35,360 --> 00:58:37,462
 PROBLEM. 

1193
00:58:37,462 --> 00:58:39,564
 THE MICE INJECTED DIED

1194
00:58:39,564 --> 00:58:45,436
 OVERNIGHT AND I MUST HAVE

1195
00:58:45,436 --> 00:58:50,375
 INJECTED SOMEWHERE THAT WAS

1196
00:58:50,375 --> 00:58:54,746
 CRITICALLY IMPORTANT.

1197
00:58:54,746 --> 00:58:58,783
 SO I INJECT AGAIN AND THE MICE

1198
00:58:58,783 --> 00:59:00,318
 DIED AGAIN.

1199
00:59:00,318 --> 00:59:02,854
 SO THREE TIMES, WE INJECT AND

1200
00:59:02,854 --> 00:59:05,456
 WITHIN A COUPLE OF HOURS, THE

1201
00:59:05,456 --> 00:59:07,425
 MOUSE IS SHIVERING.

1202
00:59:07,425 --> 00:59:10,895
 I TOUCH THE MOUSE AND SAY THE

1203
00:59:10,895 --> 00:59:12,697
 MOUSE IS COLD AND WITHIN 24

1204
00:59:12,697 --> 00:59:20,605
 HOURS, THE MOUSE DIED. 

1205
00:59:20,605 --> 00:59:31,115
 SO WE INJECT THE MOUSE AND

1206
00:59:33,051 --> 00:59:36,688
 WHEN INJECTED WITH DR3, THEY

1207
00:59:36,688 --> 00:59:38,990
 DIED WITHIN 24-48 HOURS AND

1208
00:59:38,990 --> 00:59:41,426
 NONE OF THE MICE SURVIVED OVER

1209
00:59:41,426 --> 00:59:43,027
 48 HOURS SO THAT WAS PRETTY

1210
00:59:43,027 --> 00:59:44,796
 MUCH STRIKING AND THEN THE

1211
00:59:44,796 --> 00:59:47,131
 QUESTION IS OF COURSE WHY DID

1212
00:59:47,131 --> 00:59:52,236
 THEY DIE? 

1213
00:59:52,236 --> 00:59:55,206
 SO WE INJECT THE MOUSE WHO WAS

1214
00:59:55,206 --> 01:00:01,879
 BARELY ALIVE AND HE HAD A 

1215
01:00:01,879 --> 01:00:05,750
 TREMENDOUS AMOUNT OF ALC AND

1216
01:00:05,750 --> 01:00:07,618
 TEST THE BLOOD AND BASED ON

1217
01:00:07,618 --> 01:00:10,021
 THIS, THIS LOOKS LIKE COMPLETE

1218
01:00:10,021 --> 01:00:12,390
 LIVER FAILURE AS THE MOUSE IS

1219
01:00:12,390 --> 01:00:12,924
 DYING.

1220
01:00:12,924 --> 01:00:14,525
 SO WE LOOKING FOR A SECTION

1221
01:00:14,525 --> 01:00:16,260
 AND THIS IS WHAT YOU FIND.

1222
01:00:16,260 --> 01:00:20,598
 WITHIN FIVE TO SIX HOURS, YOU

1223
01:00:20,598 --> 01:00:21,632
 SEE THIS HUMONGOUS INTILTATION

1224
01:00:21,632 --> 01:00:28,773
 OF THE CELLS IN THE LIVER AND

1225
01:00:28,773 --> 01:00:32,009
 SO THIS IS SOMETHING WE DON'T

1226
01:00:32,009 --> 01:00:33,778
 KNOW ABOUT WITH THE DR3 CELLS

1227
01:00:33,778 --> 01:00:35,613
 IN THE LIVER SO WE THOUGHT

1228
01:00:35,613 --> 01:00:39,250
 MAYBE THEY ARE ACTIVATING IT

1229
01:00:39,250 --> 01:00:45,890
 TO SUCH EXTENT THAT IT CAN

1230
01:00:45,890 --> 01:00:46,791
 CAUSE FULMINANT HEPATITIS.

1231
01:00:46,791 --> 01:00:49,827
 SO IF YOU TAKE OUT THE NKT

1232
01:00:49,827 --> 01:00:52,230
 CELLS BY THEMSELVES, WE COULD

1233
01:00:52,230 --> 01:00:57,401
 ACTUALLY RESCUE IT.

1234
01:00:57,401 --> 01:00:59,937
 SO THE GENERATION OF THE CELLS

1235
01:00:59,937 --> 01:01:09,814
 DEPENDS ON DR3 SO THE KNOCKOUT

1236
01:01:09,814 --> 01:01:13,117
 MICE WITH THIS, THE MOUSE IS

1237
01:01:13,117 --> 01:01:14,418
 NOT DYING.

1238
01:01:14,418 --> 01:01:23,327
 SO WHAT WE ARE SHOWING YOU IS 

1239
01:01:23,327 --> 01:01:31,702
 THE COINTRODUCTION OF THE ANT 

1240
01:01:31,702 --> 01:01:36,874
 TIE DR3 STIMULATION INDUCES

1241
01:01:36,874 --> 01:01:40,077
 FULMINANT HEPATITIS AND LETHAL

1242
01:01:40,077 --> 01:01:43,281
 TO VA 14 MICE.

1243
01:01:43,281 --> 01:01:45,950
 BUT ALONE IT DOESN'T DO IT SO

1244
01:01:45,950 --> 01:01:48,719
 WE THINK THE RESULTS SUGGEST

1245
01:01:48,719 --> 01:01:52,323
 THAT DR3 PROVIDES POTENT

1246
01:01:52,323 --> 01:01:53,858
 COSTIMULATORY SIGNALS TO NKT

1247
01:01:53,858 --> 01:01:54,358
 CELLS.

1248
01:01:54,358 --> 01:01:58,462
 BUT WE WANT TO KNOW WHAT IS 

1249
01:01:58,462 --> 01:02:02,834
 GOING ON WITH THE MOUSE MODEL,

1250
01:02:02,834 --> 01:02:06,270
 SO WE TEST THE COSTIMULATORY

1251
01:02:06,270 --> 01:02:09,907
 EFFECT OF DR3 IN WILD TYPE NKT

1252
01:02:09,907 --> 01:02:16,480
 CELLS SO WE INJECT THE ANTIDR3

1253
01:02:16,480 --> 01:02:17,815
 AND THEY SURVIVED.

1254
01:02:17,815 --> 01:02:18,316
 ARE THEY HAPPY?

1255
01:02:18,316 --> 01:02:18,850
 THEY ARE NOT.

1256
01:02:18,850 --> 01:02:20,585
 SO YOU CAN SEE THE INDICATION

1257
01:02:20,585 --> 01:02:23,087
 OF THE STRESS SIGNAL IN THE

1258
01:02:23,087 --> 01:02:33,664
 MOUSE BUT AFTER FOUR DAYS, OFF

1259
01:02:38,002 --> 01:02:38,369
 HEALTHY RESULT.

1260
01:02:38,369 --> 01:02:41,205
 BUT THERE IS A TINY AMOUNT AND

1261
01:02:41,205 --> 01:02:42,773
 WE LOOK INTO THE CELLS AND

1262
01:02:42,773 --> 01:02:45,276
 WHAT THEY ARE DISAPPEARING,

1263
01:02:45,276 --> 01:02:51,983
 HERE YOU SEE THE CD4 AND 5

1264
01:02:51,983 --> 01:02:57,521
 PROFILE, YOU FIND DR3 DOESN'T

1265
01:02:57,521 --> 01:03:00,391
 DO MUCH BUT THERE IS A

1266
01:03:00,391 --> 01:03:02,159
 CYTOKINE SOLUTION COMING UP.

1267
01:03:02,159 --> 01:03:04,428
 SO EVEN IN A NORMAL MOUSE, YOU

1268
01:03:04,428 --> 01:03:10,434
 HAVE A HEAVILY ACTIVATED

1269
01:03:10,434 --> 01:03:11,903
 PHENOTYPE IN THE MOUSE AND THE

1270
01:03:11,903 --> 01:03:12,970
 MICE ARE NOT HAPPY.

1271
01:03:12,970 --> 01:03:16,307
 SO WE WANT TO DO THIS IN

1272
01:03:16,307 --> 01:03:18,643
 NORMAL MOUSE WITH ACTIVATION

1273
01:03:18,643 --> 01:03:20,411
 OF NKT CELLS.

1274
01:03:20,411 --> 01:03:21,946
 SO HOW CAN WE TEST IT?

1275
01:03:21,946 --> 01:03:25,483
 SO THERE IS A MOUSE THAT IS

1276
01:03:25,483 --> 01:03:28,920
 COMPLETELY NORMAL EXCEPT FOR 

1277
01:03:28,920 --> 01:03:38,029
 THE ABSENCE OF A NKT CELL.

1278
01:03:38,029 --> 01:03:39,330
 SO WE INJECTED THESE MICE AND

1279
01:03:39,330 --> 01:03:42,700
 WANT TO SEE IF WE CAN RESCUE

1280
01:03:42,700 --> 01:03:43,968
 THE PHENOTYPE.

1281
01:03:43,968 --> 01:03:46,804
 SO WITH THE WILD TYPE MICE,

1282
01:03:46,804 --> 01:03:48,873
 AGAIN, WE INJECT AND YOU SEE

1283
01:03:48,873 --> 01:03:52,510
 THESE NUMBERS AND AFTER FOUR

1284
01:03:52,510 --> 01:03:53,544
 DAYS, YOU DEPLETE THE

1285
01:03:53,544 --> 01:03:55,279
 POPULATION BUT IN THE MOUSE

1286
01:03:55,279 --> 01:03:58,316
 THAT HAS NO NKT CELLS, THE

1287
01:03:58,316 --> 01:04:00,751
 MOUSE IS NOT AFFECTED, NUMBERS

1288
01:04:00,751 --> 01:04:03,821
 REMAIN SO WHAT THIS TELLS YOU

1289
01:04:03,821 --> 01:04:07,858
 IS THIS NKT ACTIVATION CAUSED

1290
01:04:07,858 --> 01:04:13,197
 HAVOC IN THESE MICE CREATING

1291
01:04:13,197 --> 01:04:13,597
 CYTOKINE.

1292
01:04:13,597 --> 01:04:15,967
 SO WHAT DOES IT?

1293
01:04:15,967 --> 01:04:20,271
 WE LOOK AT THESE MOUSE IN

1294
01:04:20,271 --> 01:04:20,972
 LIVER, OTHER ORGANS AND SPLEEN

1295
01:04:20,972 --> 01:04:21,906
 AND WHEN YOU LOOK AT THE FOLKS

1296
01:04:21,906 --> 01:04:32,016
 SEE OF THE NKT CELLS, THE 

1297
01:04:32,016 --> 01:04:34,218
 A-GALCER AND ANTIDR3 PRODUCE

1298
01:04:34,218 --> 01:04:38,522
 ACTIVATION OF NKT CELLS IN

1299
01:04:38,522 --> 01:04:39,890
 ENORMOUS AMOUNT AND HERE THIS

1300
01:04:39,890 --> 01:04:41,392
 HAS BEEN DOCUMENTED WITH

1301
01:04:41,392 --> 01:04:41,859
 LITERATURE.

1302
01:04:41,859 --> 01:04:46,230
 BUT WHAT WE FOUND IS IF YOU

1303
01:04:46,230 --> 01:04:49,633
 COINJECT DR3, YOU GET ABOUT 24

1304
01:04:49,633 --> 01:04:50,935
 INCREASE IN NKT CELL NUMBERS

1305
01:04:50,935 --> 01:04:57,108
 AND IN SOME CASES, WE DETECT

1306
01:04:57,108 --> 01:05:02,146
 24 TIMES IN A SPLEEN, STRONGER

1307
01:05:02,146 --> 01:05:03,280
 EXPANSION OF CELLS.

1308
01:05:03,280 --> 01:05:05,483
 BUT THE QUESTION IS ARE THESE

1309
01:05:05,483 --> 01:05:07,184
 CELLS FUNCTIONAL, ARE THEY

1310
01:05:07,184 --> 01:05:09,120
 DOING ANYTHING AND TO TEST IT,

1311
01:05:09,120 --> 01:05:11,055
 WE WANT TO LOOK AT CYTOKINE

1312
01:05:11,055 --> 01:05:12,590
 PRODUCTION AND THIS IS WHAT

1313
01:05:12,590 --> 01:05:23,134
 YOU SEE NORMALLY LOOKING AT 

1314
01:05:25,703 --> 01:05:35,279
 THE NKT CELLS, WE INJECT IL-4

1315
01:05:35,279 --> 01:05:37,214
 AND YOU SEE IT IS MUCH

1316
01:05:37,214 --> 01:05:37,548
 CLASSIC.

1317
01:05:37,548 --> 01:05:39,383
 SO NOW WE WANT TO EXPAND T

1318
01:05:39,383 --> 01:05:41,185
 CELLS, MAKE THEM ACTIVATED AND

1319
01:05:41,185 --> 01:05:44,321
 THE LAST DATA SLIDE FOR THIS

1320
01:05:44,321 --> 01:05:51,462
 ONE AND SAY WHAT CAN WE DO

1321
01:05:51,462 --> 01:05:57,768
 WITH THIS ONE AND CAN WE

1322
01:05:57,768 --> 01:06:00,404
 UTILIZE THIS ACTIVATED NKT

1323
01:06:00,404 --> 01:06:06,043
 CELL FOR THERAPEUTIC PURPOSES.

1324
01:06:06,043 --> 01:06:16,587
 SO WE TAKE THE LUNG MELANOMA

1325
01:06:20,424 --> 01:06:25,529
 MODEL, WE INJECT THE ANTIDR3

1326
01:06:25,529 --> 01:06:30,568
 AND THEN THE TWO TOGETHER AND 

1327
01:06:30,568 --> 01:06:35,506
 YOU SEE AN IMPROVED SITUATION.

1328
01:06:35,506 --> 01:06:40,111
 SO IT GETS ACTIVATED, THE NK

1329
01:06:40,111 --> 01:06:43,948
 CELL AND IT COULD BE EITHER

1330
01:06:43,948 --> 01:06:45,716
 THE MOUSE CELL OR SOMETHING

1331
01:06:45,716 --> 01:06:48,886
 ELSE, WE DON'T KNOW AND SO WE

1332
01:06:48,886 --> 01:06:52,756
 SEE THEY CAN DIRECTLY TARGET

1333
01:06:52,756 --> 01:06:54,992
 CANCER CELLS.

1334
01:06:54,992 --> 01:07:01,832
 SO WE IDENTIFY A NEW CELL 

1335
01:07:01,832 --> 01:07:04,435
 WHICH IS DR3, AND ALONE, IT

1336
01:07:04,435 --> 01:07:10,541
 CANNOT DO IT, IT AUGMENTS IT,

1337
01:07:10,541 --> 01:07:13,410
 BUT PROMOTING NKT CELL

1338
01:07:13,410 --> 01:07:17,715
 EXPANSION, CYTOKINE PRODUCTION

1339
01:07:17,715 --> 01:07:18,315
 AND ANTITUMOR ACTIVITY.

1340
01:07:18,315 --> 01:07:19,717
 SO I WANT TO CLOSE WITH THE

1341
01:07:19,717 --> 01:07:23,053
 PEOPLE WHO DID THE WORK, MOST

1342
01:07:23,053 --> 01:07:26,123
 OF THE WORK IN THE LAB AND

1343
01:07:26,123 --> 01:07:36,600
 MOST OF THE WORK DONE BY

1344
01:07:42,106 --> 01:07:43,507
 NURCIN LIMAN WHO HAD A POSTER

1345
01:07:43,507 --> 01:07:45,776
 HERE WHERE HE IS DAY BUT NOW

1346
01:07:45,776 --> 01:07:48,746
 YOU CANNOT SEE IT BUT SHE IS

1347
01:07:48,746 --> 01:07:50,648
 HERE AND I WILL TAKE

1348
01:07:50,648 --> 01:07:51,015
 QUESTIONS.

1349
01:07:51,015 --> 01:07:57,321
 >>  CAN YOU SEE ALL THE 

1350
01:07:57,321 --> 01:08:00,724
 EXPANSIONS OF NK17 AND DR3?

1351
01:08:00,724 --> 01:08:04,161
 YOU MENTIONED YOU COULD SEE IT

1352
01:08:04,161 --> 01:08:13,737
 IN THE THYMUS BUT ONLY THERE?

1353
01:08:13,737 --> 01:08:17,708
 >> YES, WE NORMALIZE THE
CELLS

1354
01:08:17,708 --> 01:08:19,743
 AND ACQUIRE PHENOTYPE WHICH WE

1355
01:08:19,743 --> 01:08:20,144
 DON'T KNOW.

1356
01:08:20,144 --> 01:08:22,213
 THE EXPANSION IS FOR ALL THREE

1357
01:08:22,213 --> 01:08:24,315
 SUBSETS, THEY ALL EXPAND.

1358
01:08:24,315 --> 01:08:26,250
 >>  THANK YOU, LOVELY
TALK.

1359
01:08:26,250 --> 01:08:33,490
 SO ARE THESE CELLS LIKELY TO

1360
01:08:33,490 --> 01:08:37,795
 HAVE NK AGENTS WHEN THEY

1361
01:08:37,795 --> 01:08:38,862
 RECOGNIZE THE LIGAND?

1362
01:08:38,862 --> 01:08:41,632
 >>  WE THINK SO, YES.

1363
01:08:41,632 --> 01:08:45,369
 >> SO THE LIGAND IS --

1364
01:08:45,369 --> 01:08:48,839
 >> NO, THOSE ARE
CONSIDERED

1365
01:08:48,839 --> 01:08:49,240
 MACRO CELLS.

1366
01:08:49,240 --> 01:08:54,945
 SOME PEOPLE TOGETHER WITH THE 

1367
01:08:54,945 --> 01:09:02,253
 GLYCOGENUINE ARE GIVEN A

1368
01:09:02,253 --> 01:09:03,721
 BOOST.

1369
01:09:03,721 --> 01:09:05,823
 >> SO THIS CAN HAVE THE

1370
01:09:05,823 --> 01:09:08,959
 RESPONSE OF PRIMARY AND

1371
01:09:08,959 --> 01:09:11,061
 SECONDARY AND IN ONE

1372
01:09:11,061 --> 01:09:12,930
 SITUATION, THE NORMAL MOUSE

1373
01:09:12,930 --> 01:09:15,966
 WILL DIE BUT THE WILD TYPE

1374
01:09:15,966 --> 01:09:23,340
 WILL NOT SO IF YOU HAVE 

1375
01:09:23,340 --> 01:09:29,913
 EXPANSION OF NKT

1376
01:09:29,913 --> 01:09:32,783
 POPULATIONS -- WILL THEY STILL

1377
01:09:32,783 --> 01:09:33,484
 LIVE?

1378
01:09:33,484 --> 01:09:39,123
 >> CAN YOU REPHRASE THE

1379
01:09:39,123 --> 01:09:40,958
 QUESTION?

1380
01:09:40,958 --> 01:09:46,664
 >> SO YOU INJECT NKT AND
--

1381
01:09:46,664 --> 01:09:47,298
 [INDISCERNIBLE]

1382
01:09:47,298 --> 01:09:50,434
 >> THAT IS A REALLY GOOD

1383
01:09:50,434 --> 01:09:50,934
 EXPERIMENT.

1384
01:09:50,934 --> 01:09:53,070
 I DIDN'T THINK ABOUT IT BUT WE

1385
01:09:53,070 --> 01:09:55,339
 SHOULD DO IT, YEAH.

1386
01:09:55,339 --> 01:09:58,242
 YOU CAN DO REPEATED INJECTION,

1387
01:09:58,242 --> 01:10:01,078
 THE DR3 LEVEL GOES DOWN

1388
01:10:01,078 --> 01:10:04,081
 BECAUSE IT IS LIGATES SO I AM

1389
01:10:04,081 --> 01:10:06,417
 NOT SURE HOW MUCH DR3.

1390
01:10:06,417 --> 01:10:08,652
 THE REASON WE DID FOUR DAYS,

1391
01:10:08,652 --> 01:10:16,327
 IF WE WAIT ONE WEEK, THE DR3

1392
01:10:16,327 --> 01:10:23,901
 COMES UP BUT EXPRESSED THE 

1393
01:10:23,901 --> 01:10:25,235
 LIBA -- LIGAND.

1394
01:10:25,235 --> 01:10:27,304
 SO WE NEED TO STUDY THIS

1395
01:10:27,304 --> 01:10:27,671
 QUESTION.

1396
01:10:27,671 --> 01:10:30,974
 >> HOW DO YOU THINK DR3
IS

1397
01:10:30,974 --> 01:10:32,876
 BEING ACTIVATED AND COULD IT

1398
01:10:32,876 --> 01:10:37,047
 NOT BE ACTIVATED TO KILL YOUR

1399
01:10:37,047 --> 01:10:38,215
 MICE?

1400
01:10:38,215 --> 01:10:42,720
 AND CONVERSELY, THE DR3

1401
01:10:42,720 --> 01:10:47,791
 KNOCKOUT AND ENKS, WHAT IT DID

1402
01:10:47,791 --> 01:10:49,360
 TO YOUR MICE?

1403
01:10:49,360 --> 01:10:54,331
 >> THE AWARD EXPERT IN
DR3, HE

1404
01:10:54,331 --> 01:10:58,369
 USED KNOCKOUT MICE AND NOW IN

1405
01:10:58,369 --> 01:11:02,106
 SWITZERLAND AND HE LEFT SO NOW

1406
01:11:02,106 --> 01:11:05,142
 WE ARE BREEDING THIS MOUSE.

1407
01:11:05,142 --> 01:11:08,879
 THE CONDITION IS THE DR3 IN

1408
01:11:08,879 --> 01:11:10,781
 THE BREEDING, THAT IS ONE

1409
01:11:10,781 --> 01:11:11,148
 QUESTION.

1410
01:11:11,148 --> 01:11:17,488
 BUT WE THINK THE BR3 ON

1411
01:11:17,488 --> 01:11:19,123
 DENDRITIC CELLS WILL PRODUCE

1412
01:11:19,123 --> 01:11:19,823
 THE SIGNAL.

1413
01:11:19,823 --> 01:11:23,427
 WE ARE NOT SURE ABOUT TR1A.

1414
01:11:23,427 --> 01:11:33,771
 I THINK THE CELL THAT PREVENTS

1415
01:11:33,771 --> 01:11:35,672
 THE GLYCOGEN --

1416
01:11:35,672 --> 01:11:36,273
 [INDISCERNIBLE]

1417
01:11:36,273 --> 01:11:36,874
 GREAT QUESTION.

1418
01:11:36,874 --> 01:11:37,741
 >>  TWO QUESTIONS.

1419
01:11:37,741 --> 01:11:41,044
 IF I RECALL DR3 MADE THE

1420
01:11:41,044 --> 01:11:43,981
 BIGGEST DIFFERENCE IN T L1 A

1421
01:11:43,981 --> 01:11:47,084
 IN EXPANSION OF T CELLS IN THE

1422
01:11:47,084 --> 01:11:49,520
 PERIPHERY IN INFLAMED ORGAN.

1423
01:11:49,520 --> 01:11:50,020
 >> YES.

1424
01:11:50,020 --> 01:11:51,054
 >> SAVES WONDERING DO YOU
SEE

1425
01:11:51,054 --> 01:11:52,823
 A DIFFERENCE IN THE SPLEEN

1426
01:11:52,823 --> 01:11:54,792
 VERSUS IN PERIPHERAL ORGANS

1427
01:11:54,792 --> 01:11:57,094
 AND, TWO, DO YOU KNOW ANYTHING

1428
01:11:57,094 --> 01:12:00,964
 MUCH ABOUT WHAT SIGNALING

1429
01:12:00,964 --> 01:12:03,333
 PATHWAYS ARE ACTIVATED

1430
01:12:03,333 --> 01:12:05,102
 DOWNSTREAM OF DR3.

1431
01:12:05,102 --> 01:12:07,070
 >> SO THE SECOND
QUESTION,

1432
01:12:07,070 --> 01:12:10,741
 WHAT IS DOWNSTREAM, THE DR3

1433
01:12:10,741 --> 01:12:11,775
 HAS THREE PATHWAYS AND THE

1434
01:12:11,775 --> 01:12:13,944
 MOST IMPORTANT THING IS WE

1435
01:12:13,944 --> 01:12:21,618
 COULD INHIBIT THIS EFFECT

1436
01:12:21,618 --> 01:12:22,386
 USING CHYNASE CONTRIBUTOR.

1437
01:12:22,386 --> 01:12:25,322
 THE SECOND THING IS ABOUT T

1438
01:12:25,322 --> 01:12:26,089
 CELL ACTIVATION.

1439
01:12:26,089 --> 01:12:28,492
 DR3 IS ACTUALLY EXPRESSED IN

1440
01:12:28,492 --> 01:12:32,329
 HIGHER AMOUNT OF T CELLS AND

1441
01:12:32,329 --> 01:12:34,164
 THOSE ARE THE THINGS WE ALSO

1442
01:12:34,164 --> 01:12:38,235
 DID BUT THE DIFFERENCE IS IN T

1443
01:12:38,235 --> 01:12:40,337
 CELLS, MOST OF THEM EXPAND AND

1444
01:12:40,337 --> 01:12:42,139
 THEY ARE NOT FUNCTIONAL.

1445
01:12:42,139 --> 01:12:45,242
 THEY ACTUALLY CANNOT DO

1446
01:12:45,242 --> 01:12:46,076
 ANYTHING.

1447
01:12:46,076 --> 01:12:48,145
 OUR ENK CELLS CAN EXPAND AND

1448
01:12:48,145 --> 01:12:50,180
 DO SOMETHING SO I THINK THAT

1449
01:12:50,180 --> 01:12:58,455
 IS THE DIFFERENCE.

1450
01:12:58,455 --> 01:12:58,822
 [APPLAUSE]

1451
01:12:58,822 --> 01:13:01,959
 >> SO IT IS A PLEASURE TO

1452
01:13:01,959 --> 01:13:04,561
 INTRODUCE OUR NEXT SPEAKER

1453
01:13:04,561 --> 01:13:07,865
 COMING ALL THE WAY FROM THE

1454
01:13:07,865 --> 01:13:18,442
 WEST COAST AND GOING TO TALK 

1455
01:13:54,244 --> 01:13:55,679
 ABOUT MEMORY RESPONSES.

1456
01:13:55,679 --> 01:13:56,914
 >>> OKAY, THANK YOU
VERY MUCH,

1457
01:13:56,914 --> 01:13:59,182
 THANK YOU FOR THE INVITATION.

1458
01:13:59,182 --> 01:14:00,817
 THE MEETING HAS BEEN GREAT,

1459
01:14:00,817 --> 01:14:02,419
 WONDERFUL TO BE HERE AND I AM

1460
01:14:02,419 --> 01:14:06,456
 VERY IMPRESSED WITH THE OTHER

1461
01:14:06,456 --> 01:14:06,823
 SPEAKERS.

1462
01:14:06,823 --> 01:14:09,993
 I WILL TRY NOT TO DISAPPOINT

1463
01:14:09,993 --> 01:14:10,661
 YOU.

1464
01:14:10,661 --> 01:14:13,664
 THIS WORK IS DONE BY A NUMBER

1465
01:14:13,664 --> 01:14:17,267
 OF PEOPLE AND I WILL MENTION 

1466
01:14:17,267 --> 01:14:27,811
 SOME NATION QUICKLY, GABRIEL

1467
01:14:30,080 --> 01:14:32,182
 ASCUI-GAC, MALL REMURRAY, AND

1468
01:14:32,182 --> 01:14:32,716
 OF COURSE FUNDING.

1469
01:14:32,716 --> 01:14:35,152
 I CONSULT FOR A COMPANY THAT

1470
01:14:35,152 --> 01:14:40,924
 WANTS TO DO NKT CELL THERAPY

1471
01:14:40,924 --> 01:14:43,460
 SO THAT IS MY DISCLOSURE.

1472
01:14:43,460 --> 01:14:46,830
 THIS TOPIC HAS BEEN INTRODUCED

1473
01:14:46,830 --> 01:14:48,832
 AND WE HAVE GONE THROUGH THE

1474
01:14:48,832 --> 01:14:51,735
 SUBSETS THAT SEEM TO, IN SOME

1475
01:14:51,735 --> 01:14:54,471
 PEOPLE'S MINDS, IN BETWEEN

1476
01:14:54,471 --> 01:14:56,773
 INNATE AND ADAPTIVE IMMUNITY

1477
01:14:56,773 --> 01:15:00,010
 AND THAT INCLUDES THE GAMMA

1478
01:15:00,010 --> 01:15:04,081
 AND BETA CELLS AND TWO TYPES

1479
01:15:04,081 --> 01:15:04,514
 OF NKT CELLS.

1480
01:15:04,514 --> 01:15:07,284
 I WILL TALK ABOUT NKT CELLS

1481
01:15:07,284 --> 01:15:11,088
 AND WHAT ARE CALLED MUCOSAL

1482
01:15:11,088 --> 01:15:12,189
 INVARY UNITED T CELLS.

1483
01:15:12,189 --> 01:15:14,124
 ONE OF THE STRIKING THINGS

1484
01:15:14,124 --> 01:15:16,226
 ABOUT THESE CELLS WHICH HAS

1485
01:15:16,226 --> 01:15:19,129
 MOTIVATED OUR WORK OVER MANY 

1486
01:15:19,129 --> 01:15:20,597
 YEARS IS THE CONSERVATION

1487
01:15:20,597 --> 01:15:23,033
 WHICH I WILL SAY MY LAB FOUND

1488
01:15:23,033 --> 01:15:24,067
 MANY YEARS AGO.

1489
01:15:24,067 --> 01:15:28,105
 SO IN OTHER WORDS MOUSE AND

1490
01:15:28,105 --> 01:15:30,374
 HUMAN NKT CELLS ARE NEARLY

1491
01:15:30,374 --> 01:15:31,842
 IDENTICAL.

1492
01:15:31,842 --> 01:15:34,578
 IN FACT, THERE'S INTEREST

1493
01:15:34,578 --> 01:15:35,479
 INTERSPECIES CROSS REACTIVITY

1494
01:15:35,479 --> 01:15:37,347
 SO THESE HAVE BEEN PRESERVED

1495
01:15:37,347 --> 01:15:39,650
 FOR TENS OF MILLIONS OF YEARS

1496
01:15:39,650 --> 01:15:41,351
 IN EVOLUTION.

1497
01:15:41,351 --> 01:15:43,487
 BECAUSE OF THE CONSERVATION,

1498
01:15:43,487 --> 01:15:44,921
 THESE WILL NOT CAUSE DISEASE

1499
01:15:44,921 --> 01:15:46,356
 AND THERE ARE A LOT OF

1500
01:15:46,356 --> 01:15:48,525
 ATTEMPTS TO USE THESE KIND OF

1501
01:15:48,525 --> 01:15:54,965
 CELLS IN VARIOUS CANCER IMMUNE

1502
01:15:54,965 --> 01:15:58,368
 THERAPIES, IN OTHER WORDS

1503
01:15:58,368 --> 01:16:01,805
 THERAPIES WITH ANTIGENS OR

1504
01:16:01,805 --> 01:16:06,943
 CELL-BASED OR VAC ACT

1505
01:16:06,943 --> 01:16:17,320
 VARIETIES -- ACTIV ATORS.

1506
01:16:17,320 --> 01:16:19,790
 SO WE LOOK AT THE PROPERTIES

1507
01:16:19,790 --> 01:16:28,098
 OF NKT AND MAIT CELLS, THE

1508
01:16:28,098 --> 01:16:36,406
 MICROBIAL REACTIVITY TO

1509
01:16:36,406 --> 01:16:38,008
 NONPEPTIDE ANTIGENS, THEY MAKE

1510
01:16:38,008 --> 01:16:40,744
 RAPID RESPONSES AND CAN BE

1511
01:16:40,744 --> 01:16:45,282
 ACTIVATED BY CYTOKINES SUCH AS

1512
01:16:45,282 --> 01:16:52,422
 IL18, VERY MUCH LIKE ILC OR

1513
01:16:52,422 --> 01:16:52,789
 ENK CELLS.

1514
01:16:52,789 --> 01:16:55,992
 SO A FEW YEARS AGO WE LOOKED

1515
01:16:55,992 --> 01:16:58,295
 AT NKT CELLS WITH SURFACE

1516
01:16:58,295 --> 01:16:59,796
 MARKERS THAT WOULD

1517
01:16:59,796 --> 01:17:01,198
 DIFFERENTIATE THEM AND FOR

1518
01:17:01,198 --> 01:17:05,635
 EXAMPLE WE HAVE A SUBSET OF

1519
01:17:05,635 --> 01:17:12,676
 NKT CELLS AND A ROW OF T CELLS

1520
01:17:12,676 --> 01:17:16,913
 AND WE INPUT SINGLE SELL

1521
01:17:16,913 --> 01:17:22,552
 RNASEQ AND IN TRIP KATE, WHAT

1522
01:17:22,552 --> 01:17:23,954
 IS THE TONE?

1523
01:17:23,954 --> 01:17:24,488
 OKAY, NEITHER DO I.

1524
01:17:24,488 --> 01:17:27,390
 IT IS MY TIMER, I THINK.

1525
01:17:27,390 --> 01:17:31,962
 SO ALL OF THESE ARE DIFFERENT 

1526
01:17:31,962 --> 01:17:35,565
 AND HIGHLY POSITIVE CELLS

1527
01:17:35,565 --> 01:17:42,939
 WITHIN THE MICE WITH

1528
01:17:42,939 --> 01:17:47,544
 TRANSCRIPTOMIC RELATIVITY.

1529
01:17:47,544 --> 01:17:52,382
 SO THEN WHAT MALL REMURRAY AND

1530
01:17:52,382 --> 01:17:54,184
 SCOTT BROWN AND OTHERS DID, WE

1531
01:17:54,184 --> 01:17:58,021
 LOOKED AT THE NKT CELLS IN

1532
01:17:58,021 --> 01:18:02,159
 DIFFERENT ORGANS, LIVER, LUNG,

1533
01:18:02,159 --> 01:18:04,294
 SPLEEN AND THYMUS AND SORTED

1534
01:18:04,294 --> 01:18:11,134
 THEM AND YOU CAN SEE HERE BY 

1535
01:18:11,134 --> 01:18:14,037
 ATAC-SEQ AND RNA-SEQ, THE DATA

1536
01:18:14,037 --> 01:18:14,604
 BELOW.

1537
01:18:14,604 --> 01:18:15,405
 BUT SOME CELLS CLUSTER, NOT

1538
01:18:15,405 --> 01:18:22,179
 WHERE THEY ARE BUT

1539
01:18:22,179 --> 01:18:23,713
 PREDOMINANTLY, PREDOMINANTLY

1540
01:18:23,713 --> 01:18:26,983
 BY THE SUBSET.

1541
01:18:26,983 --> 01:18:32,756
 SO WHETHER IT IS LUNG, SPLEEN,

1542
01:18:32,756 --> 01:18:36,159
 THYMUS, NKT1 IS MORE SIMILAR

1543
01:18:36,159 --> 01:18:37,961
 THAN NKT2 AND SOME OF THE

1544
01:18:37,961 --> 01:18:41,398
 SPLEEN DATA IS SHOWN BELOW.

1545
01:18:41,398 --> 01:18:42,699
 BY TRANSCRIPTION, THE LUNG

1546
01:18:42,699 --> 01:18:45,869
 CELLS TEND TO BE SOMEWHAT

1547
01:18:45,869 --> 01:18:47,137
 DIFFERENT IN THIS DIMENSION AS

1548
01:18:47,137 --> 01:18:49,906
 SEEN HERE.

1549
01:18:49,906 --> 01:18:50,640
 BUT NEVERTHELESS, THE

1550
01:18:50,640 --> 01:18:54,277
 FUNCTIONAL THING IS THE SUBSET

1551
01:18:54,277 --> 01:18:57,180
 AND THAT MIGHT LEAD TO A MODEL

1552
01:18:57,180 --> 01:18:59,549
 THAT MAYBE THESE CELLS ARE

1553
01:18:59,549 --> 01:19:00,217
 PREFIXED.

1554
01:19:00,217 --> 01:19:02,385
 THERE ARE SOME SIGNALS THAT

1555
01:19:02,385 --> 01:19:03,920
 HAVE BEEN DEFINED SUCH AS

1556
01:19:03,920 --> 01:19:05,488
 CYTOKINES AND THEN AFTER THAT,

1557
01:19:05,488 --> 01:19:07,958
 THEY GO AFTER TISSUE, THEY SIT

1558
01:19:07,958 --> 01:19:10,160
 IN THE TISSUES AND THEY DON'T

1559
01:19:10,160 --> 01:19:11,161
 CHANGE.

1560
01:19:11,161 --> 01:19:11,761
 ARE THEY FIXED?

1561
01:19:11,761 --> 01:19:13,296
 AND THE FACT OF THE MATTER IS

1562
01:19:13,296 --> 01:19:19,936
 THEY ARE NOT FIXED.

1563
01:19:19,936 --> 01:19:21,972
 AND, OKAY, I WILL JUST GO.

1564
01:19:21,972 --> 01:19:28,311
 SO THIS IS WHAT NKT CELLS LOOK

1565
01:19:28,311 --> 01:19:38,889
 LIKE IN UNIMMUNIZED MICE, AND

1566
01:19:39,389 --> 01:19:42,025
 YOU SEE PD1, YOU HAVE A HUGE

1567
01:19:42,025 --> 01:19:45,262
 POPULATION KNOWN AS NKT HELPER

1568
01:19:45,262 --> 01:19:48,131
 CELLS AND IN FACT A NUMBER OF

1569
01:19:48,131 --> 01:19:49,199
 GROUPS HAVE CHARACTERIZED

1570
01:19:49,199 --> 01:19:50,433
 THESE CELLS PREVIOUSLY AND

1571
01:19:50,433 --> 01:19:52,269
 THEY ACTUALLY DO FUNCTION AS

1572
01:19:52,269 --> 01:19:53,536
 HELPERS FOR B CELLS.

1573
01:19:53,536 --> 01:19:55,105
 AND THEN THERE'S ANOTHER GROUP

1574
01:19:55,105 --> 01:19:57,073
 DOWN HERE THAT DIDN'T HAVE

1575
01:19:57,073 --> 01:19:57,941
 THOSE MARKERS SPECIAL THOSE

1576
01:19:57,941 --> 01:19:59,609
 CELLS, AS I WILL TELL YOU,

1577
01:19:59,609 --> 01:20:00,810
 ALSO TURN OUT TO BE DIFFERENT

1578
01:20:00,810 --> 01:20:03,647
 AND THIS IS A 6-DAY ANALYSIS.

1579
01:20:03,647 --> 01:20:11,888
 SO IF YOU LOOK AT THESE

1580
01:20:11,888 --> 01:20:21,364
 ANTIGENIC EXPERIENCED CELLS

1581
01:20:21,364 --> 01:20:24,534
 AND ATAC-SEQ, YOU SEE THEY ARE

1582
01:20:24,534 --> 01:20:26,436
 HIGHLY DIFFERENTIATED AND ARE

1583
01:20:26,436 --> 01:20:30,240
 DIFFERENT FROM ANYTHING THAT 

1584
01:20:30,240 --> 01:20:32,509
 EXISTED BEFORE, NKT1, 2 OR 17.

1585
01:20:32,509 --> 01:20:34,177
 THIS OTHER POPULATION REALLY

1586
01:20:34,177 --> 01:20:36,680
 EXPRESSES A LOT OF THE MARKERS

1587
01:20:36,680 --> 01:20:39,449
 OF AN ACTIVATED K CELL, HIGH

1588
01:20:39,449 --> 01:20:41,584
 LEVEL OF EXPRESSION OF NK

1589
01:20:41,584 --> 01:20:43,086
 RECEPTORS AND SO ON.

1590
01:20:43,086 --> 01:20:45,488
 SO IT LOOKED LIKE THE ANTIGEN

1591
01:20:45,488 --> 01:20:47,657
 MADE TWO POPULATIONS, A HELPER

1592
01:20:47,657 --> 01:20:50,860
 POPULATION AND AN EFFECTIVE

1593
01:20:50,860 --> 01:20:52,262
 POPULATION AFTER THE

1594
01:20:52,262 --> 01:20:53,930
 STIMULATION EVENT AND THIS WAS

1595
01:20:53,930 --> 01:20:56,399
 DONE AT 6 DAYS AND WE NOW HAVE

1596
01:20:56,399 --> 01:20:57,901
 SINGLE CELL DATA FROM 30 DAYS

1597
01:20:57,901 --> 01:21:00,437
 AND I WON'T GO OVER ALL THAT

1598
01:21:00,437 --> 01:21:02,072
 TODAY BUT WHAT I CAN SHOW YOU

1599
01:21:02,072 --> 01:21:04,341
 IS THAT THESE POPULATIONS

1600
01:21:04,341 --> 01:21:04,708
 PERSIST.

1601
01:21:04,708 --> 01:21:05,942
 SO AT SIX DAYS IN THE SPLEEN,

1602
01:21:05,942 --> 01:21:13,616
 WE HAVE THE POPULATION OF NKT

1603
01:21:13,616 --> 01:21:15,185
 EFFECTORS, AND THE SAME THING

1604
01:21:15,185 --> 01:21:16,219
 FOR THE HELPER.

1605
01:21:16,219 --> 01:21:18,254
 THE ANTIGEN HAS A HALF LIFE

1606
01:21:18,254 --> 01:21:21,124
 AROUND 18 HOURS SO WE BELIEVE

1607
01:21:21,124 --> 01:21:24,327
 THEN THESE ARE TRANSCRIPTIONAL

1608
01:21:24,327 --> 01:21:25,795
 AND GENOMIC CHANGES THAT

1609
01:21:25,795 --> 01:21:27,764
 PERSIST AND GIVE RISE TO

1610
01:21:27,764 --> 01:21:29,866
 FUNCTIONAL CHANGES AND NEW

1611
01:21:29,866 --> 01:21:31,401
 SUBSETS OF CELLS.

1612
01:21:31,401 --> 01:21:33,703
 SO WE MIGHT CALL THESE CELLS

1613
01:21:33,703 --> 01:21:35,839
 MEMORY, MIGHT CALL THEM

1614
01:21:35,839 --> 01:21:38,375
 ANTIGEN ADAPTED, WE MIGHT CALL

1615
01:21:38,375 --> 01:21:39,376
 THEM TRAINED, NOT SURE WHAT

1616
01:21:39,376 --> 01:21:40,810
 THE BEST WORD IS BUT THE POINT

1617
01:21:40,810 --> 01:21:42,645
 IS YOU HAVE A POPULATION THAT

1618
01:21:42,645 --> 01:21:45,115
 DEVELOPS IN THE THYMUS WHICH

1619
01:21:45,115 --> 01:21:47,817
 IS A KIND OF EFFECTOR CELL AND

1620
01:21:47,817 --> 01:21:50,253
 YET THEY ARE CAPABLE OF

1621
01:21:50,253 --> 01:21:50,754
 LONG-TERM CHANGES.

1622
01:21:50,754 --> 01:21:53,189
 SO I WILL SPEND THE REST OF

1623
01:21:53,189 --> 01:21:58,061
 THE TALK ON MAIT CELLS AND

1624
01:21:58,061 --> 01:22:02,932
 THESE ARE QUITE SIMILAR AND

1625
01:22:02,932 --> 01:22:11,074
 THIS WORK IS DONE BY GABRIEL

1626
01:22:11,074 --> 01:22:14,377
 ASCUI-GAC AND SHILPI CHANDRA.

1627
01:22:14,377 --> 01:22:20,383
 SO THE MOUTH MAIT CELLS ARE

1628
01:22:20,383 --> 01:22:23,653
 BORN EFFECTOR CELLS, YOU HAVE

1629
01:22:23,653 --> 01:22:26,189
 THE MAIT1 AND 17 AND YOU CAN

1630
01:22:26,189 --> 01:22:32,962
 SEE WE HAVE THE IL17A AND IFNY

1631
01:22:32,962 --> 01:22:35,331
 AND LOOKING AT FOUR TISSUES,

1632
01:22:35,331 --> 01:22:38,401
 LIVER, LUNG, SPLEEN AND THYMUS

1633
01:22:38,401 --> 01:22:42,572
 AND YOU CAN SEE THERE ARE TWO 

1634
01:22:42,572 --> 01:22:46,543
 SUBSETS, A MAIT1 AND MAIT17

1635
01:22:46,543 --> 01:22:56,219
 AND THE THIGH MUSCLE IS CONTRI 

1636
01:22:56,219 --> 01:23:01,958
 -- THYMUS IS SHOWING THE

1637
01:23:01,958 --> 01:23:08,498
 SIGNATURE WITH THE MAIT1 OR

1638
01:23:08,498 --> 01:23:09,065
 MAIT17 TRANSCRIPTOME.

1639
01:23:09,065 --> 01:23:10,834
 SO THE QUESTION IS ARE THESE

1640
01:23:10,834 --> 01:23:13,436
 CELLS PREFIXED OR NOT?

1641
01:23:13,436 --> 01:23:15,004
 AND HERE WE ADOPTED THROUGH

1642
01:23:15,004 --> 01:23:23,113
 THE WORK OF ALEXANDER CORBETT

1643
01:23:23,113 --> 01:23:26,549
 AND MELVIN, THIS IS A MODEL

1644
01:23:26,549 --> 01:23:29,385
 WHERE WE GIVE SOME MON ELLA IN

1645
01:23:29,385 --> 01:23:33,990
 THE LUNG AND THIS CAUSES A

1646
01:23:33,990 --> 01:23:39,896
 HUGE NUMBER OF MAIT CELLS

1647
01:23:39,896 --> 01:23:41,898
 WHICH STAY GREATLY ELEVATED

1648
01:23:41,898 --> 01:23:42,899
 FOR MONTHS.

1649
01:23:42,899 --> 01:23:44,367
 WE KEPT USING THIS SYSTEM

1650
01:23:44,367 --> 01:23:46,002
 BECAUSE IT IS VERY EFFECTIVE

1651
01:23:46,002 --> 01:23:56,579
 BUT WE CAN DO THE SAME THING 

1652
01:23:58,481 --> 01:24:04,220
 WITH THE F.TULARENSIS AND IT

1653
01:24:04,220 --> 01:24:08,591
 DOESN'T HAVE TO STAY IN THE

1654
01:24:08,591 --> 01:24:13,496
 LUNG BUT PERSISTS AND SO SAM

1655
01:24:13,496 --> 01:24:15,165
 MON ELLA HAS AN ANTIGEN AND

1656
01:24:15,165 --> 01:24:17,367
 YOU CAN SEE AFTER NINE WEEKS,

1657
01:24:17,367 --> 01:24:19,936
 IF WE RE INFECT, THE CFU IN

1658
01:24:19,936 --> 01:24:21,704
 THE LUNG ARE MUCH LOWER

1659
01:24:21,704 --> 01:24:24,307
 COMPARED TO THE SO-CALLED

1660
01:24:24,307 --> 01:24:28,077
 NAIVE MADE CELLS AND IF WE

1661
01:24:28,077 --> 01:24:37,921
 EXPERIMENT HERE, USE A

1662
01:24:37,921 --> 01:24:39,889
 DIFFERENT BACTERIAL,

1663
01:24:39,889 --> 01:24:45,195
 S.PNEUMONIA AND YOU CAN SEE

1664
01:24:45,195 --> 01:24:46,162
 THE MAIT CELLS.

1665
01:24:46,162 --> 01:24:49,132
 SO WE KNOW THE BACTERIA ARE

1666
01:24:49,132 --> 01:24:56,239
 CLEARED, WE USE A QUORUM

1667
01:24:56,239 --> 01:24:58,241
 SENSING BACTERIA AND YOU STILL

1668
01:24:58,241 --> 01:24:59,142
 GET THE EXPANSION SO IT IS NOT

1669
01:24:59,142 --> 01:25:01,611
 A QUESTION AND WE HAVE DONE

1670
01:25:01,611 --> 01:25:05,181
 OTHER EXPERIMENTS AS WELL.

1671
01:25:05,181 --> 01:25:11,688
 SO WE DID THE RNA-SEQ AFTER 40

1672
01:25:11,688 --> 01:25:14,824
 DAYS OF THE SALMONELLA

1673
01:25:14,824 --> 01:25:17,026
 INFECTION, YOU CAN SEE THE

1674
01:25:17,026 --> 01:25:18,528
 CELLS CLUSTERED AND ONCE AGAIN

1675
01:25:18,528 --> 01:25:23,466
 THEY FIT INTO TH1 AND TH17

1676
01:25:23,466 --> 01:25:26,402
 TRANSCRIPTOMES AS YOU SEE

1677
01:25:26,402 --> 01:25:36,579
 HERE. 

1678
01:25:38,748 --> 01:25:43,086
 AND THESE TWO RECEPTORS HAVE

1679
01:25:43,086 --> 01:25:44,487
 GOOD EXPRESSION.

1680
01:25:44,487 --> 01:25:46,356
 THESE ARE FAIRLY GOOD SURFACE

1681
01:25:46,356 --> 01:25:49,859
 MARKERS THAT ALLOW US TO 

1682
01:25:49,859 --> 01:25:51,527
 SEPARATE THE MAIT17'S WHICH IS

1683
01:25:51,527 --> 01:25:58,067
 WHAT WE CALL THEM FROM THE

1684
01:25:58,067 --> 01:25:58,434
 MAIT1'S.

1685
01:25:58,434 --> 01:26:01,471
 SO THEY ARRIVE LATE FROM THE

1686
01:26:01,471 --> 01:26:03,706
 INFECTION AND A FAIRLY POP

1687
01:26:03,706 --> 01:26:06,109
 LIESD SUBSET.

1688
01:26:06,109 --> 01:26:07,810
 BY DAY 67, SEEMS LIKE THEY ARE

1689
01:26:07,810 --> 01:26:18,354
 TURNING OVER AND IF YOU DO A

1690
01:26:18,721 --> 01:26:22,859
 CD INJECTION, MANY OF THEM ARE

1691
01:26:22,859 --> 01:26:33,436
 IN THE BLOOD WHILE IL17 ARE IN

1692
01:26:42,578 --> 01:26:42,845
 THE BLOOD.

1693
01:26:42,845 --> 01:26:47,850
 SO THIS IS AN IL17 FATE

1694
01:26:47,850 --> 01:26:50,820
 KNOCKOUT MOUSE IF YOU WILL AND

1695
01:26:50,820 --> 01:26:55,692
 THIS IS THE ININFECTED MAIT

1696
01:26:55,692 --> 01:26:58,094
 CELLS IN THE MOUSE AND MOST

1697
01:26:58,094 --> 01:27:02,432
 ARE INACTIVE MEANING THEY HAVE

1698
01:27:02,432 --> 01:27:04,367
 MADE ENOUGH CELLS IN THE

1699
01:27:04,367 --> 01:27:05,768
 BLOOD.

1700
01:27:05,768 --> 01:27:12,608
 IF WE LOOK 40 DAYS AFTER 

1701
01:27:12,608 --> 01:27:14,243
 RECEPTION, THE EFFECTOR

1702
01:27:14,243 --> 01:27:24,987
 POSITIVE CELLS -- I THINK IT 

1703
01:27:24,987 --> 01:27:32,261
 IS MY OWN MOUSE ACTUALLY. 

1704
01:27:32,261 --> 01:27:33,496
 LET ME SEE.

1705
01:27:33,496 --> 01:27:34,831
 YES, YOU SHOULD HAVE

1706
01:27:34,831 --> 01:27:35,298
 INTERRUPTED ME.

1707
01:27:35,298 --> 01:27:37,633
 IT TOOK ME 20 MINUTES TO

1708
01:27:37,633 --> 01:27:39,669
 FIGURE IT OUT.

1709
01:27:39,669 --> 01:27:43,906
 ALL RIGHT, SO THESE STAYED

1710
01:27:43,906 --> 01:27:46,876
 POSITIVE, THE ILG1 CELLS, THEY

1711
01:27:46,876 --> 01:27:51,114
 NEVER MADE IL17, OKAY? 

1712
01:27:51,114 --> 01:27:56,686
 SO THESE CELLS HAVE DIFFERENT

1713
01:27:56,686 --> 01:27:58,254
 ABILITIES TO PROTECT AND SO

1714
01:27:58,254 --> 01:28:01,958
 WHAT WE DID IS PUT THESE

1715
01:28:01,958 --> 01:28:11,834
 EXPANDED CELLS IN THE KLRG1 OR

1716
01:28:11,834 --> 01:28:14,737
 CD127 -- I AM JUST GOING TO GO

1717
01:28:14,737 --> 01:28:15,571
 WITH IT.

1718
01:28:15,571 --> 01:28:18,141
 THANK YOU FOR PUTTING UP WITH

1719
01:28:18,141 --> 01:28:18,541
 ME.

1720
01:28:18,541 --> 01:28:20,877
 WHERE AM I WITH TIME, BY THE

1721
01:28:20,877 --> 01:28:21,144
 WAY?

1722
01:28:21,144 --> 01:28:21,544
 OKAY, GOOD.

1723
01:28:21,544 --> 01:28:23,146
 SO THIS IS A TRANSFER

1724
01:28:23,146 --> 01:28:25,047
 EXPERIMENT AND WE'RE LOOKING

1725
01:28:25,047 --> 01:28:30,987
 AT PROTECTION HERE AND THE

1726
01:28:30,987 --> 01:28:35,158
 IL17 RECEPTOR PROTECT AGAINST

1727
01:28:35,158 --> 01:28:36,058
 PNEUMONIA.

1728
01:28:36,058 --> 01:28:39,562
 THIS IS MEASURED AFTER TWO

1729
01:28:39,562 --> 01:28:46,669
 DAYS AND THE IL CELLS DID NOT.

1730
01:28:46,669 --> 01:28:57,246
 WE ALSO DID AN INFLUENZA VIRUS

1731
01:28:58,181 --> 01:29:01,584
 AND YOU SEE THAT EXPRESSED

1732
01:29:01,584 --> 01:29:01,884
 THERE.

1733
01:29:01,884 --> 01:29:04,020
 IT TURNS OUT IT IS NOT UNUSUAL

1734
01:29:04,020 --> 01:29:07,990
 THAT THEY ACT DIFFERENTLY

1735
01:29:07,990 --> 01:29:13,996
 BECAUSE THEY ARE DIFFERENT IN

1736
01:29:13,996 --> 01:29:15,965
 THEIR METABOLISM. 

1737
01:29:15,965 --> 01:29:20,136
 MAIT17 CELLS TAKE UP FATTY

1738
01:29:20,136 --> 01:29:22,772
 ACIDS AND HAVE MITOCHONDRIAL

1739
01:29:22,772 --> 01:29:26,375
 ACTIVITY WHICH YOU SEE HERE.

1740
01:29:26,375 --> 01:29:30,413
 YOU HAVE THE CD127 AND THIS IS

1741
01:29:30,413 --> 01:29:32,982
 STAYING LOWER WITH THE

1742
01:29:32,982 --> 01:29:34,851
 RECEPTIVE POSITIVE ONES

1743
01:29:34,851 --> 01:29:36,519
 STAYING HIGHER.

1744
01:29:36,519 --> 01:29:46,929
 AND THEN IN THIS MICROSCOPY,

1745
01:29:46,929 --> 01:29:57,373
 THAT IS NOT MINE -- YEAH.

1746
01:29:57,373 --> 01:30:07,650
 [ OFF MIC ] 

1747
01:30:11,521 --> 01:30:13,389
 OKAY, THANK YOU.

1748
01:30:13,389 --> 01:30:14,891
 [LAUGHTER]

1749
01:30:14,891 --> 01:30:18,194
 SO IN ANY CASE, THIS IS THE

1750
01:30:18,194 --> 01:30:21,297
 FATTY AS SIT UPTAKE AND THIS

1751
01:30:21,297 --> 01:30:26,569
 IS THE MITOCHONDRIAL COUNT.

1752
01:30:26,569 --> 01:30:34,644
 SO OF COURSE THE MAIT17 CELLS 

1753
01:30:34,644 --> 01:30:40,383
 HAVE THE FATTY ACID UPTAKE AND

1754
01:30:40,383 --> 01:30:44,487
 MIGHT DON'T -- MITOCHONDRIAL

1755
01:30:44,487 --> 01:30:46,822
 ACTIVITY AND THESE CELLS HAVE

1756
01:30:46,822 --> 01:30:48,357
 A HIGHER CONCENTRATION RATE

1757
01:30:48,357 --> 01:30:50,693
 AND THEY HAVE MORE NPK.

1758
01:30:50,693 --> 01:30:54,964
 SO BASICALLY THEY HAVE MORE 

1759
01:30:54,964 --> 01:30:57,199
 ACTIVE MIGHT DON'T --

1760
01:30:57,199 --> 01:30:58,467
 MITOCHONDRIA AND WHEN WE PUT

1761
01:30:58,467 --> 01:31:08,945
 THESE IN ARE A VERY LOW

1762
01:31:11,447 --> 01:31:13,482
 NUTRIENT MATERIAL, IT WILL

1763
01:31:13,482 --> 01:31:17,486
 ELEVATE THEIR SURVIVAL WHILE

1764
01:31:17,486 --> 01:31:18,888
 THE MAIT1 CELLS, WHEN WE ARE

1765
01:31:18,888 --> 01:31:23,459
 GAVE THEM THE NUTRIENT

1766
01:31:23,459 --> 01:31:26,395
 SUPPLEMENT, IT WAS NOT AS

1767
01:31:26,395 --> 01:31:26,762
 DRAMATIC.

1768
01:31:26,762 --> 01:31:30,900
 AND THEN YOU HAVE THESE

1769
01:31:30,900 --> 01:31:34,904
 TRANSGENIC MICE AND YOU CAN 

1770
01:31:34,904 --> 01:31:37,773
 SEE THE MAIT17 CELLS HAVE

1771
01:31:37,773 --> 01:31:40,610
 HELPED TO MAINTAIN

1772
01:31:40,610 --> 01:31:41,043
 MITOCHONDRIA.

1773
01:31:41,043 --> 01:31:42,678
 ADDITIONALLY IF WE LOOK IN

1774
01:31:42,678 --> 01:31:47,984
 VITRO AT THEIR ABILITY TO 

1775
01:31:47,984 --> 01:31:51,220
 RESPOND, THE MAIT17 CELLS

1776
01:31:51,220 --> 01:32:01,564
 RESPOND ON FATTY ACIDS AND YOU

1777
01:32:01,564 --> 01:32:05,768
 CAN SEE HERE IT IS HIGHLY

1778
01:32:05,768 --> 01:32:13,476
 SUBJECTED TO THE INHIBITOR AND

1779
01:32:13,476 --> 01:32:20,082
 THE INTERFEREON RESPONSE WAS

1780
01:32:20,082 --> 01:32:23,552
 HIGHLY DEPENDENT ON THE

1781
01:32:23,552 --> 01:32:24,320
 GLUCOSE.

1782
01:32:24,320 --> 01:32:26,122
 SO FINALLY DOES METABOLISM

1783
01:32:26,122 --> 01:32:30,559
 MATTER AND WE LOOKED AT

1784
01:32:30,559 --> 01:32:41,137
 KNOCKOUTS TO LOOK AT THE HIF1A

1785
01:32:46,208 --> 01:32:51,380
 WHICH WILL STABILIZE AND YOU

1786
01:32:51,380 --> 01:32:57,219
 CAN SEE THE MAIT17 CELLS AND 

1787
01:32:57,219 --> 01:33:06,128
 THEIR ABILITY TO MAKE MAIT17

1788
01:33:06,128 --> 01:33:13,302
 BUT NOT SO MUCH IN THE MAIT1.

1789
01:33:13,302 --> 01:33:16,806
 SO WE LOOKED AT THE TISSUE

1790
01:33:16,806 --> 01:33:17,540
 SPECIFIC TRANSCRIPTION

1791
01:33:17,540 --> 01:33:21,177
 SIGNATURES FOR HUMAN MAIT

1792
01:33:21,177 --> 01:33:30,753
 CELLS, YOU CAN SEE, WE HAVE

1793
01:33:30,753 --> 01:33:33,856
 THE DIFFERENT CLUSTERS AND

1794
01:33:33,856 --> 01:33:37,927
 SOME APPEAR TO BE PROLIFERATED

1795
01:33:37,927 --> 01:33:38,728
 IN THE BLOOD.

1796
01:33:38,728 --> 01:33:43,165
 SO ARE THEY LIKE THE MICE MAIT

1797
01:33:43,165 --> 01:33:46,602
 CELLS OR MAYBE THEY ARE NOT?

1798
01:33:46,602 --> 01:33:49,071
 SO HERE WE LOOK AT THE LUNG,

1799
01:33:49,071 --> 01:33:51,006
 THE RESULTS ARE THE SAME FROM

1800
01:33:51,006 --> 01:33:55,411
 THE BLOOD AND THE MAIT17 CELLS

1801
01:33:55,411 --> 01:33:58,647
 DO TAKE UP FATTY ACIDS, THEY

1802
01:33:58,647 --> 01:34:00,983
 HAVE A BIT OF TISSUE MEMORY,

1803
01:34:00,983 --> 01:34:04,920
 DIFFERENT FROM THE NAIVE CELLS

1804
01:34:04,920 --> 01:34:06,322
 BUT THE MITOCHONDRIAL

1805
01:34:06,322 --> 01:34:07,923
 POTENTIAL IS NOT ELEVATED LIKE

1806
01:34:07,923 --> 01:34:10,459
 IT WAS IN THE MOUSE SO IT

1807
01:34:10,459 --> 01:34:13,362
 LOOKS LIKE IT HAS A DIFFERENT

1808
01:34:13,362 --> 01:34:14,997
 METABOLIC PROFILE AND THEN

1809
01:34:14,997 --> 01:34:18,434
 WHEN WE LOOK AT THE

1810
01:34:18,434 --> 01:34:19,702
 TRANSCRIPTOME OF THE AGGREGATE

1811
01:34:19,702 --> 01:34:21,804
 OF THE FOUR DIFFERENT ORGANS,

1812
01:34:21,804 --> 01:34:25,741
 YOU DON'T SEE THE CLEAR MAIT1

1813
01:34:25,741 --> 01:34:27,409
 OR 17 PHENOTYPE AND I THINK

1814
01:34:27,409 --> 01:34:29,345
 THE QUESTION REMAINS WHETHER

1815
01:34:29,345 --> 01:34:31,280
 THESE SUBSETS EXIST IN HUMANS.

1816
01:34:31,280 --> 01:34:36,385
 HOWEVER THIS IS THIS RECENT 

1817
01:34:36,385 --> 01:34:41,323
 PAPER THAT LOOKED AT PNEUMONIA

1818
01:34:41,323 --> 01:34:42,691
 IN ADULTS AND YOUNGER CHILDREN

1819
01:34:42,691 --> 01:34:45,961
 AND MOST OF THE MAIT CELLS HAD

1820
01:34:45,961 --> 01:34:55,571
 THE CAPACITY TO MAKE IL AND

1821
01:34:55,571 --> 01:34:58,607
 THIS FOES DOWN WITH AGE AND IN

1822
01:34:58,607 --> 01:35:02,044
 A CERTAIN CONTEXT, YOU SEE THE

1823
01:35:02,044 --> 01:35:03,112
 MAIT17 CELLS.

1824
01:35:03,112 --> 01:35:05,447
 SO TO SUMMARIZE, THERE ARE

1825
01:35:05,447 --> 01:35:10,186
 ANTIGEN OR MEMORY-LIKE T

1826
01:35:10,186 --> 01:35:12,321
 CELLS, THEY REQUIRE EFFECTOR

1827
01:35:12,321 --> 01:35:16,492
 PROGRAMS IN THE THYMUS, CAN

1828
01:35:16,492 --> 01:35:18,160
 GIVE RISE TO NEW CELLS.

1829
01:35:18,160 --> 01:35:25,267
 AND FOR THE MAIT CELLS, THE

1830
01:35:25,267 --> 01:35:26,202
 RESPONSES ARE PREVALENT AT

1831
01:35:26,202 --> 01:35:28,237
 LEAST IN THE MOUSE AND THE

1832
01:35:28,237 --> 01:35:32,908
 HUMAN APPEARS SO FAR TO BE

1833
01:35:32,908 --> 01:35:33,776
 INTRAVENOUS BUT WE DON'T

1834
01:35:33,776 --> 01:35:36,445
 REALLY HAVE THE EQUIVALENT OF

1835
01:35:36,445 --> 01:35:38,781
 THE KIND OF INFECTION THAT I

1836
01:35:38,781 --> 01:35:41,417
 TOLD YOU ABOUT IN THE MOUSE SO

1837
01:35:41,417 --> 01:35:42,651
 THAT LEAVES AN OPEN QUESTION

1838
01:35:42,651 --> 01:35:53,095
 AND THANK YOU FOR YOUR

1839
01:35:53,295 --> 01:35:55,164
 ATTENTION.

1840
01:35:55,164 --> 01:35:55,764
 [APPLAUSE]

1841
01:35:55,764 --> 01:35:56,465
 >> HELLO.

1842
01:35:56,465 --> 01:36:02,004
 I AM WONDERING ABOUT THE

1843
01:36:02,004 --> 01:36:02,504
 INKTFH CELL.

1844
01:36:02,504 --> 01:36:04,306
 IF YOU CHECK ON THE FUNCTION

1845
01:36:04,306 --> 01:36:06,308
 OF THEM, BECAUSE SINCE THEY

1846
01:36:06,308 --> 01:36:07,509
 ARE EXPRESSING, GIVING THE

1847
01:36:07,509 --> 01:36:12,014
 SAME MARKERS OF THE TSH'S, IT

1848
01:36:12,014 --> 01:36:16,719
 MORE OR LESS COULD ALSO MAIT

1849
01:36:16,719 --> 01:36:18,921
 FUNCTION IF YOU TESTED THEM,

1850
01:36:18,921 --> 01:36:21,991
 LIKE YOU SEE IN OTHER ORGANS

1851
01:36:21,991 --> 01:36:22,892
 FOR EXAMPLE THE LYMPH NODES

1852
01:36:22,892 --> 01:36:26,395
 AND ALSO THE SPLEEN?

1853
01:36:26,395 --> 01:36:27,696
 >> YEAH, SO I MENTIONED
WORK

1854
01:36:27,696 --> 01:36:29,798
 FROM OTHER PAPERS THAT CON

1855
01:36:29,798 --> 01:36:30,733
 SADD THAT AND PEOPLE HAVE

1856
01:36:30,733 --> 01:36:33,535
 SHOWN THEY ARE CAPABLE OF

1857
01:36:33,535 --> 01:36:40,409
 HELPING T CELLS IN BOTH A 

1858
01:36:40,409 --> 01:36:41,677
 PROGNATE AND NONPROGNATE

1859
01:36:41,677 --> 01:36:43,879
 FASHION, THEY EXPAND QUICKLY

1860
01:36:43,879 --> 01:36:46,382
 SO WE DIDN'T DO A LOT OF THAT

1861
01:36:46,382 --> 01:36:46,682
 WORK.

1862
01:36:46,682 --> 01:36:49,084
 I CAN TELL YOU THERE ARE MANY

1863
01:36:49,084 --> 01:36:50,452
 MORE OF THEM IN THE SPLEEN

1864
01:36:50,452 --> 01:36:52,054
 THAN THE LIVER AND THE LUNG

1865
01:36:52,054 --> 01:36:56,292
 BUT CAN ALSO FIND THEM IN THE

1866
01:36:56,292 --> 01:36:57,726
 LYMPH CELLS SO THEY ARE AS YOU

1867
01:36:57,726 --> 01:37:02,798
 WOULD EXPECT THEM TO BE.

1868
01:37:02,798 --> 01:37:04,300
 >> THANK YOU.

1869
01:37:04,300 --> 01:37:05,501
 >> MITCH, VERY NICE TALK.

1870
01:37:05,501 --> 01:37:08,470
 ACTUALLY I HAD A QUESTION.

1871
01:37:08,470 --> 01:37:11,573
 DO THE MAIT17 CELLS EXPRESS

1872
01:37:11,573 --> 01:37:14,043
 IL17 RECEPTOR AND DO THEY PLAY

1873
01:37:14,043 --> 01:37:24,586
 ANY ROLE IN OUGHT OUGHT -- 

1874
01:37:29,024 --> 01:37:31,193
 AUTO IMMUNITY RECEPTOR?

1875
01:37:31,193 --> 01:37:34,830
 >> THEY DO PLAY A ROLE IN
AUTO

1876
01:37:34,830 --> 01:37:35,731
 IMMUNITY RECEPTORS AND THERE

1877
01:37:35,731 --> 01:37:39,935
 WAS A PAPER RECENTLY THAT SAID

1878
01:37:39,935 --> 01:37:41,537
 THEY CONTROL ROT IN THE BRAIN

1879
01:37:41,537 --> 01:37:46,608
 AND IN THE ABSENCE OF MAIT

1880
01:37:46,608 --> 01:37:50,980
 CELLS, YOU DEVELOP ROT IN THE

1881
01:37:50,980 --> 01:37:53,282
 MENINGES AND YOU GET

1882
01:37:53,282 --> 01:37:57,086
 INFILTRATION, TAKES SIX MONTHS

1883
01:37:57,086 --> 01:37:59,288
 AND MIGHT REPORT ON THE

1884
01:37:59,288 --> 01:37:59,922
 DEFECT.

1885
01:37:59,922 --> 01:38:01,256
 I BROUGHT THAT UP BECAUSE I

1886
01:38:01,256 --> 01:38:04,426
 KNOW YOU ARE INTERESTED IN

1887
01:38:04,426 --> 01:38:05,027
 NEUROINFLAMMATION.

1888
01:38:05,027 --> 01:38:08,697
 WE ONLY HAVE WORKED IN

1889
01:38:08,697 --> 01:38:10,332
 INFECTIOUS MODELS SO WE

1890
01:38:10,332 --> 01:38:11,600
 OURSELVES HAVE NOT DONE

1891
01:38:11,600 --> 01:38:12,868
 ANYTHING ON THAT.

1892
01:38:12,868 --> 01:38:13,902
 >> THANK YOU.

1893
01:38:13,902 --> 01:38:22,211
 >>  I HAVE A QUICK
QUESTION.

1894
01:38:22,211 --> 01:38:25,280
 YOU SAID THE --

1895
01:38:25,280 --> 01:38:26,048
 [INDISCERNIBLE]

1896
01:38:26,048 --> 01:38:28,317
 >> IS THE MEMORY
SYSTEMIC?

1897
01:38:28,317 --> 01:38:29,785
 IT IS.

1898
01:38:29,785 --> 01:38:33,889
 SO WE DID AN INHALATION MODEL

1899
01:38:33,889 --> 01:38:35,958
 BUT SAW SOME MEMORY IN THE

1900
01:38:35,958 --> 01:38:38,627
 LIVER AND WE DID LESS SO IN

1901
01:38:38,627 --> 01:38:44,767
 OTHER ORGANS AND WE HAVE ALSO 

1902
01:38:44,767 --> 01:38:46,535
 LOOKED AT FRANSISLLA WHERE YOU

1903
01:38:46,535 --> 01:38:57,112
 COULD SEE MEMORY MADE CELLS IN

1904
01:39:00,449 --> 01:39:03,218
 DIFFERENT ORGANS.

1905
01:39:03,218 --> 01:39:03,552
 >> OKAY.

1906
01:39:03,552 --> 01:39:03,952
 [ OFF MIC ]

1907
01:39:03,952 --> 01:39:06,321
 >> THE COMPUTER IS OFF,
OKAY.

1908
01:39:06,321 --> 01:39:07,890
 >> SO I WILL INTRODUCE
OUR

1909
01:39:07,890 --> 01:39:18,467
 LAST SPEAKER FOR THE MORNING 

1910
01:39:54,203 --> 01:39:55,037
 SESSION FROM CORNELL.

1911
01:39:55,037 --> 01:39:56,738
 >> OKAY, THANK YOU VERY
MUCH,

1912
01:39:56,738 --> 01:40:02,211
 HI EVERYONE MY NAME IS DAVID

1913
01:40:02,211 --> 01:40:03,879
 FROM WALL GROUND NEW YORK,

1914
01:40:03,879 --> 01:40:05,314
 GREAT PLEASURE TO BE HERE.

1915
01:40:05,314 --> 01:40:07,583
 I WAS GETTING READY IT TH-RPBG

1916
01:40:07,583 --> 01:40:08,650
 AND WAS THINKING EVERY TIME I

1917
01:40:08,650 --> 01:40:12,254
 COME TO THE D.C. AREA, CRAZY

1918
01:40:12,254 --> 01:40:12,888
 STUFF HAPPENS.

1919
01:40:12,888 --> 01:40:15,491
 YOU KNOW, GOVERNMENT SHUTDOWN,

1920
01:40:15,491 --> 01:40:16,925
 CRAZY DEBATE THAT I DIDN'T

1921
01:40:16,925 --> 01:40:19,928
 SEE, JUST SAW THE EDITED

1922
01:40:19,928 --> 01:40:21,563
 HIGHLIGHTS AND THEN I REALIZED

1923
01:40:21,563 --> 01:40:22,998
 NO, IT IS NOT EVERY TIME I

1924
01:40:22,998 --> 01:40:24,967
 COME, IT IS JUST EVERY DAY IN

1925
01:40:24,967 --> 01:40:31,406
 THE D.C. AREA SO FOR OUR NIH

1926
01:40:31,406 --> 01:40:34,009
 FOLKS, THANK YOU FOR

1927
01:40:34,009 --> 01:40:35,310
 ORGANIZING THE EVENT AND

1928
01:40:35,310 --> 01:40:45,654
 PUTTING UP WITH THE CRAZINESS.

1929
01:40:45,654 --> 01:40:50,192
 AND SO I THANK YOU ALL, I KNOW

1930
01:40:50,192 --> 01:40:52,928
 THIS IS A TREMENDOUS AMOUNT OF

1931
01:40:52,928 --> 01:40:54,463
 WORK BEHIND THE SCENES.

1932
01:40:54,463 --> 01:40:58,667
 SO I WILL GIVE YOU A QUICK

1933
01:40:58,667 --> 01:41:01,537
 HIGHLIGHT OF RECENT STUDIES IN

1934
01:41:01,537 --> 01:41:07,809
 THE LAB THAT DEAL WITH

1935
01:41:07,809 --> 01:41:10,679
 REGULATION AND I WAS BEING

1936
01:41:10,679 --> 01:41:21,256
 AMBITIOUS TO SHARE SOME OF THE

1937
01:41:22,157 --> 01:41:24,393
 INFORMATION BUT THANKS TO THE

1938
01:41:24,393 --> 01:41:27,029
 OTHER SPEAKERS, I CAN MAKE MY

1939
01:41:27,029 --> 01:41:27,429
 SHORT.

1940
01:41:27,429 --> 01:41:32,668
 SO I WILL TALK ABOUT THE

1941
01:41:32,668 --> 01:41:33,368
 EPITHELIAL INTERACTIONS, THE

1942
01:41:33,368 --> 01:41:34,069
 NEUROIMMUNE CIRCUITS IN THE

1943
01:41:34,069 --> 01:41:38,941
 GUT AND THEN DIET AND INNATE

1944
01:41:38,941 --> 01:41:39,308
 IMMUNITY.

1945
01:41:39,308 --> 01:41:41,109
 HOPEFULLY MY COMPUTER BEHAVES

1946
01:41:41,109 --> 01:41:42,244
 ITSELF.

1947
01:41:42,244 --> 01:41:44,580
 THE EARLY WORK WE DID AND MANY

1948
01:41:44,580 --> 01:41:45,447
 OTHER LABS DID THE SAME

1949
01:41:45,447 --> 01:41:53,488
 ANALYSIS TO LOOK AT 

1950
01:41:53,488 --> 01:41:54,957
 TRANSCRIPTIONAL PROFILES OF

1951
01:41:54,957 --> 01:41:57,025
 CELLS AND IF I GO BACK TO THE

1952
01:41:57,025 --> 01:41:58,994
 INTRODUCTION, WHEN I STARTED

1953
01:41:58,994 --> 01:42:04,032
 IN MY PH.D. MANY YEARS AGO,

1954
01:42:04,032 --> 01:42:06,535
 MUCOSAL IMMUNOLOGY WAS ON A

1955
01:42:06,535 --> 01:42:08,103
 VERY RESTRICTED NUMBER OF CELL

1956
01:42:08,103 --> 01:42:11,473
 TYPES AND WE ARE JUST NOW

1957
01:42:11,473 --> 01:42:13,709
 BEGINNING TO UNDERSTAND THE

1958
01:42:13,709 --> 01:42:15,310
 CROSS TALK BETWEEN THE

1959
01:42:15,310 --> 01:42:17,379
 ESPECIALLY TEAL CRIMINAL AND

1960
01:42:17,379 --> 01:42:18,213
 NEUROIMMUNE INTERACTIONS WHICH

1961
01:42:18,213 --> 01:42:19,381
 WE CAN TALK ABOUT.

1962
01:42:19,381 --> 01:42:23,919
 SO THE EARLY WORK WE DID 

1963
01:42:23,919 --> 01:42:29,291
 LOOKING AT ILCS, PURIFIED FROM

1964
01:42:29,291 --> 01:42:32,628
 TISSUE AND LOOKING AT THE

1965
01:42:32,628 --> 01:42:33,395
 TRANSCRIPTIONAL PROFILES.

1966
01:42:33,395 --> 01:42:38,066
 THIS IS BULK RNA-SEQ THAT WE

1967
01:42:38,066 --> 01:42:42,871
 DID TO SORT THE ILC2'S AND

1968
01:42:42,871 --> 01:42:49,177
 THIS IS FROM EITHER THE LUNG,

1969
01:42:49,177 --> 01:42:59,655
 SMALL INTESTINE, LARGE 

1970
01:43:00,789 --> 01:43:03,525
 INTESTINE, HAD AIP -- AND

1971
01:43:03,525 --> 01:43:06,395
 ADIPOSE AND YOU CAN SEE IT IS

1972
01:43:06,395 --> 01:43:09,665
 QUITE DIFFERENT DEPENDING ON

1973
01:43:09,665 --> 01:43:16,571
 WHICH ILC2'S WE LOOK IN.

1974
01:43:16,571 --> 01:43:18,573
 COLON ILC2 EXHIBITS GREENS

1975
01:43:18,573 --> 01:43:19,808
 MOST DIFFERENTIALLY EXPRESSED

1976
01:43:19,808 --> 01:43:22,911
 IN THE COLON ASSOCIATED WITH

1977
01:43:22,911 --> 01:43:30,185
 WOUND HEALING AND REPAIR TO

1978
01:43:30,185 --> 01:43:31,320
 HOMEOSTASIS.

1979
01:43:31,320 --> 01:43:32,921
 LUNG ILC2'S PARTICULARLY

1980
01:43:32,921 --> 01:43:37,025
 ENRICHED IN GENES REGULATED BY

1981
01:43:37,025 --> 01:43:38,827
 IL-33 AND GROWTH FACTOR

1982
01:43:38,827 --> 01:43:44,766
 SIGNALING AND THEN THE ADIPOSE

1983
01:43:44,766 --> 01:43:50,939
 TISSUE ILC2'S SPECIFICALLY

1984
01:43:50,939 --> 01:43:56,311
 EXPRESSED IN METABOLIC-RELATED

1985
01:43:56,311 --> 01:43:56,712
 GENES.

1986
01:43:56,712 --> 01:44:00,148
 SO AS WAS POINTED OUT, THESE

1987
01:44:00,148 --> 01:44:07,222
 COME FROM DIFFERENT SITES OF 

1988
01:44:07,222 --> 01:44:09,558
 THE BODY AND TISSUE-SPECIFIC

1989
01:44:09,558 --> 01:44:12,894
 IN THE MICRO BIOME IN WHICH

1990
01:44:12,894 --> 01:44:13,295
 THEY RESIDE.

1991
01:44:13,295 --> 01:44:23,839
 SO LOOKING AT THE ILC2'S AND

1992
01:44:27,342 --> 01:44:37,786
 ADOPTIVE TRANSFER, WE LOOKED

1993
01:44:38,353 --> 01:44:40,322
 SIMILARLY TO PROTECTIVE TYPE

1994
01:44:40,322 --> 01:44:42,657
 RESPONSES. 

1995
01:44:42,657 --> 01:44:46,194
 WE ALSO KNOW THEY ARE

1996
01:44:46,194 --> 01:44:49,364
 IMPORTANT IN THE TISSUE REPAIR

1997
01:44:49,364 --> 01:44:49,831
 AND HOMEOSTASIS.

1998
01:44:49,831 --> 01:45:00,409
 SO THIS IS IN A MICE MODEL OF

1999
01:45:05,213 --> 01:45:08,550
 DSS, TOXIC IN DRINKING WATER

2000
01:45:08,550 --> 01:45:13,688
 AND IS A GREAT MODEL FOR ACUTE

2001
01:45:13,688 --> 01:45:14,890
 INTESTINAL DAMAGE,

2002
01:45:14,890 --> 01:45:16,124
 INFLAMMATION AND REPAIR AND

2003
01:45:16,124 --> 01:45:18,460
 HERE IN THE INTEREST OF TIME,

2004
01:45:18,460 --> 01:45:20,862
 I WILL SHOW YOU THE TISSUE

2005
01:45:20,862 --> 01:45:24,900
 THAT SHOWS THE WHOLE STORY.

2006
01:45:24,900 --> 01:45:26,568
 THE BLUE-PURPLE STAIN YOU SEE

2007
01:45:26,568 --> 01:45:29,905
 HERE, THE WILD TYPE

2008
01:45:29,905 --> 01:45:32,741
 ABNORMALITIES -- ANIMALS

2009
01:45:32,741 --> 01:45:36,144
 EXPOSED TO DSS ARE MUCH MORE

2010
01:45:36,144 --> 01:45:46,555
 DRAMATIC IN THIS TISSUE REPAIR

2011
01:45:46,555 --> 01:45:48,356
 FOR THE ILC2.

2012
01:45:48,356 --> 01:45:53,929
 IF WE RESTORE TO AREGULIN, WE

2013
01:45:53,929 --> 01:46:02,270
 CAN SEE THE REPAIR AND IF WE 

2014
01:46:02,270 --> 01:46:05,106
 TRANSFER THE AREGULIN WITH THE

2015
01:46:05,106 --> 01:46:07,175
 ILC2, IT DOESN'T WORK.

2016
01:46:07,175 --> 01:46:09,377
 SO THE WORK EMERGING FROM MANY

2017
01:46:09,377 --> 01:46:12,247
 FIELD IN THE LAST DECADE, WE

2018
01:46:12,247 --> 01:46:14,983
 BEGIN TO RECOGNIZE THE

2019
01:46:14,983 --> 01:46:18,019
 EXTERNAL FACTORS LIKE

2020
01:46:18,019 --> 01:46:22,090
 CYTOKINES, GROWTH FACTORS,

2021
01:46:22,090 --> 01:46:28,330
 PROSTAGLANDINS THAT CAN BE

2022
01:46:28,330 --> 01:46:31,066
 ACTIVE EFFECTORS AND IN THE

2023
01:46:31,066 --> 01:46:34,836
 LOWER PANEL, THEY CAN BE

2024
01:46:34,836 --> 01:46:36,371
 DEPEND ENT ON THE FUNCTION OF

2025
01:46:36,371 --> 01:46:41,443
 THE TISSUE IN WHICH THEY ARE

2026
01:46:41,443 --> 01:46:43,311
 FOUND.

2027
01:46:43,311 --> 01:46:53,889
 SO YOU SEE IMMUNOGLOBULIN, THE

2028
01:46:57,459 --> 01:46:59,694
 CONTROL OF MET TAB LYNN SO

2029
01:46:59,694 --> 01:47:08,770
 THESE CELLS ALL DRIVE FROM THE

2030
01:47:08,770 --> 01:47:09,838
 COMMON REGENERAL ENITOR BUT

2031
01:47:09,838 --> 01:47:12,073
 ALL THE TISSUES THEY ARE IN.

2032
01:47:12,073 --> 01:47:21,883
 SO I WAS DISCUSSING WITH 

2033
01:47:21,883 --> 01:47:26,888
 ANOTHER SCIENTIST,

2034
01:47:26,888 --> 01:47:30,625
 CHRISITOPH KLOSE, HOW DO THESE

2035
01:47:30,625 --> 01:47:39,434
 REGULATE IN THEIR FUNCTIONS

2036
01:47:39,434 --> 01:47:43,772
 AND PERHAPS IT IS THEIR

2037
01:47:43,772 --> 01:47:48,710
 COUNTERPARTS BUT AS JIM SAID, 

2038
01:47:48,710 --> 01:47:50,011
 IT IS MORE THE PATHWAY.

2039
01:47:50,011 --> 01:47:52,414
 SO I WILL SHOW YOU A LITTLE

2040
01:47:52,414 --> 01:47:55,116
 IMAGING TO CUT TO THE CHASE TO

2041
01:47:55,116 --> 01:47:58,186
 IDENTIFY BE WITH THE GUT AND

2042
01:47:58,186 --> 01:48:02,357
 OTHER BARRIER SURFACES, ILC2'S

2043
01:48:02,357 --> 01:48:04,259
 ARE PARTICULARLY ASSOCIATED

2044
01:48:04,259 --> 01:48:04,993
 WITH THE INNERVATION.

2045
01:48:04,993 --> 01:48:10,699
 IN THE GUT AS YOU KNOW, THIS 

2046
01:48:10,699 --> 01:48:16,471
 IS THE INTRINSIC AND ENTERIC

2047
01:48:16,471 --> 01:48:17,238
 CIRCUITS.

2048
01:48:17,238 --> 01:48:18,340
 NEUROSCIENTISTS TELL ME THERE

2049
01:48:18,340 --> 01:48:20,241
 ARE MORE INDIVIDUAL NEURONS IN

2050
01:48:20,241 --> 01:48:24,079
 THE CELL BODIES THAN THERE ARE

2051
01:48:24,079 --> 01:48:26,815
 IN THE GUT OR SENSORY SYSTEM.

2052
01:48:26,815 --> 01:48:28,550
 I DON'T KNOW IF THAT IS TRUE

2053
01:48:28,550 --> 01:48:31,019
 OR SOMETHING THEY JUST LIKE TO

2054
01:48:31,019 --> 01:48:33,321
 TELL GRADUATES BUT EITHER WAY,

2055
01:48:33,321 --> 01:48:37,492
 YOU CAN SEE THEY ARE HIGHLY

2056
01:48:37,492 --> 01:48:38,526
 EXPRESS ANT HERE.

2057
01:48:38,526 --> 01:48:44,733
 THIS IS JUST CLARITY OF GUT

2058
01:48:44,733 --> 01:48:55,176
 TISSUE AND THEN WE'RE 

2059
01:48:58,546 --> 01:48:59,214
 VISUALIZING THE CHOLINERGIC

2060
01:48:59,214 --> 01:48:59,848
 NEURONS IN RED.

2061
01:48:59,848 --> 01:49:06,688
 SO THE CENTRAL PART IS THE

2062
01:49:06,688 --> 01:49:13,395
 LUMEN AND THE EXTERNAL PART IS

2063
01:49:13,395 --> 01:49:14,129
 THE CHOLINERGIC NEURONS AND

2064
01:49:14,129 --> 01:49:18,733
 YOU CAN SEE IT IS ALL THE WAY

2065
01:49:18,733 --> 01:49:23,104
 THROUGH THE SUBMUCOSA AND INTO

2066
01:49:23,104 --> 01:49:24,005
 THE INTESTINE ITSELF.

2067
01:49:24,005 --> 01:49:29,678
 AND ON THE RIGHT, YOU CAN SEE

2068
01:49:29,678 --> 01:49:34,249
 THE COLLOCALIZATION OF THE LIN

2069
01:49:34,249 --> 01:49:35,917
 AND KLRG1 AND CLOSELY

2070
01:49:35,917 --> 01:49:38,353
 ASSOCIATED WITH THE NEURONS.

2071
01:49:38,353 --> 01:49:40,455
 SO WE ASKED THEN IS THERE ANY

2072
01:49:40,455 --> 01:49:43,058
 FUNCTIONAL SIGNIFICANCE TO

2073
01:49:43,058 --> 01:49:53,034
 THIS, SO DO NEUROPEPTIDES 

2074
01:49:53,034 --> 01:49:56,738
 DERIVE FROM THE NEURONS AND SO

2075
01:49:56,738 --> 01:50:07,282
 HERE IS AN ILC C2 WITH IL13

2076
01:50:09,718 --> 01:50:12,554
 AND HOPEFULLY A SHORT EXPOSURE

2077
01:50:12,554 --> 01:50:15,623
 PROMOTES THE EXPANSION OF IL2

2078
01:50:15,623 --> 01:50:18,993
 CELLS AND IF WE COMPARE THAT

2079
01:50:18,993 --> 01:50:22,197
 TO THE CLASSIC STIMULATION OF

2080
01:50:22,197 --> 01:50:27,035
 IL2, 7 AND 33 OR WITH

2081
01:50:27,035 --> 01:50:28,436
 BIOLOGICAL STIMULATION WITH

2082
01:50:28,436 --> 01:50:33,441
 THE MOUSING, YOU SEE IN A 

2083
01:50:33,441 --> 01:50:43,952
 SHORT PERIOD OF TIME, THE

2084
01:50:45,153 --> 01:50:48,189
 EFFECT ON INFECTION.

2085
01:50:48,189 --> 01:50:51,059
 WE CAN DO THIS ON OTHER TYPES

2086
01:50:51,059 --> 01:50:54,129
 OF INFECTION AND I AM SHOWING

2087
01:50:54,129 --> 01:50:57,198
 YOU THE GLOB LET CELL RESPONSE

2088
01:50:57,198 --> 01:50:59,701
 HERE ON THE LEFT TO VISUALIZE

2089
01:50:59,701 --> 01:51:02,237
 THAT AND THEN THE PARASITES

2090
01:51:02,237 --> 01:51:05,573
 USED TO ACTIVATE THE ILC2'S.

2091
01:51:05,573 --> 01:51:11,513
 THIS IS RATHER ILC2 DEPEND ENT

2092
01:51:11,513 --> 01:51:19,053
 AND AN NNMU ROW ZEST TO BE IS

2093
01:51:19,053 --> 01:51:29,264
 CRITICAL -- A NMU RECEPTION IS

2094
01:51:29,264 --> 01:51:30,698
 REQUIRED.

2095
01:51:30,698 --> 01:51:35,637
 SO THEN THERE ARE A FEW PAPERS

2096
01:51:35,637 --> 01:51:37,138
 ON THE SELECTIVE EXPRESSION

2097
01:51:37,138 --> 01:51:45,747
 AND REQUIREMENT OF NMUR1 ON 

2098
01:51:45,747 --> 01:51:50,185
 ILC2'S IN MULTIPLE TISSUES FOR

2099
01:51:50,185 --> 01:51:54,989
 THE GUT AND LYMPHOID CELLS.

2100
01:51:54,989 --> 01:52:01,262
 SO WE SEE THE INNATE AND

2101
01:52:01,262 --> 01:52:02,864
 ADAPTIVE IMMUNITY, WOULD WE

2102
01:52:02,864 --> 01:52:13,408
 FIND IT IS VERY MICROBIO AND

2103
01:52:20,715 --> 01:52:21,883
 ENVIRONMENTAL STIMULATION.

2104
01:52:21,883 --> 01:52:30,758
 SO WE ASK IF THERE ARE A 

2105
01:52:30,758 --> 01:52:31,826
 REQUIREMENT FOR ILC2 CELLS OR

2106
01:52:31,826 --> 01:52:34,929
 IF THERE IS A HANGOVER PRIOR

2107
01:52:34,929 --> 01:52:39,901
 TO THE DEVELOPMENT OF ANTIGEN

2108
01:52:39,901 --> 01:52:41,703
 RECEPTORS IN ADAPTIVE

2109
01:52:41,703 --> 01:52:46,841
 POPULATIONS AND CERTAINLY ONE

2110
01:52:46,841 --> 01:52:52,146
 COULD MAKE A COMPARISON IN THE

2111
01:52:52,146 --> 01:52:53,214
 ILC2 CELLS, THE ONLY

2112
01:52:53,214 --> 01:52:56,818
 DIFFERENCE BEING THE PRESENCE

2113
01:52:56,818 --> 01:52:58,720
 OF ANTIGEN RECEPTORS.

2114
01:52:58,720 --> 01:53:02,223
 SO A BUNCH OF WAYS TO ASK WITH

2115
01:53:02,223 --> 01:53:05,860
 BONE TRANSFERS AND CHIMERAS,

2116
01:53:05,860 --> 01:53:08,463
 ALL DONE OVER THE YEARS BEFORE

2117
01:53:08,463 --> 01:53:10,031
 BUT SOMEWHAT LIMITED BECAUSE

2118
01:53:10,031 --> 01:53:11,032
 THEY ARE IMPERFECT.

2119
01:53:11,032 --> 01:53:14,469
 SO THERE HAS ALWAYS BEEN THIS

2120
01:53:14,469 --> 01:53:19,007
 STRIDE OF NOT PERFECT BUT 

2121
01:53:19,007 --> 01:53:29,584
 CLOSER TO PERFECT GENETIC TOOL

2122
01:53:30,118 --> 01:53:30,551
 TO SHOW THESE.

2123
01:53:30,551 --> 01:53:34,188
 SO THIS IS WORK DONE IN THE

2124
01:53:34,188 --> 01:53:35,957
 LAB AND HERE WE WERE LOOKING

2125
01:53:35,957 --> 01:53:43,431
 AT EXPRESSION OF THE RECEPTOR

2126
01:53:43,431 --> 01:53:46,501
 FOR NMU, THE UP WITH I JUST

2127
01:53:46,501 --> 01:53:49,137
 TOLD -- THE ONE I JUST TOLD

2128
01:53:49,137 --> 01:53:56,244
 YOU ABOUT AND HERE THE NMU 

2129
01:53:56,244 --> 01:53:59,881
 RECEPTOR ARE LOOKING ALMOST

2130
01:53:59,881 --> 01:54:01,816
 IDENTICAL AND WHERE THEY ARE

2131
01:54:01,816 --> 01:54:02,650
 MOST ACTIVE APPEARANCE PEERS

2132
01:54:02,650 --> 01:54:13,194
 TO BE THE ILC2 POPULATION. 

2133
01:54:13,494 --> 01:54:23,037
 SO REINSERT A ILC2 RECEPTOR

2134
01:54:23,037 --> 01:54:25,173
 AND IT SEEMS TO WORK FAIRLY

2135
01:54:25,173 --> 01:54:25,540
 WELL.

2136
01:54:25,540 --> 01:54:29,644
 ON THE RIGHT THE FLAVORS AND 

2137
01:54:29,644 --> 01:54:33,281
 THEN THE RECEPTOR, EGFP

2138
01:54:33,281 --> 01:54:36,217
 APPEARS TO NICELY BE COLLECTED

2139
01:54:36,217 --> 01:54:38,786
 BUT THEN IF YOU LOOK AT THE

2140
01:54:38,786 --> 01:54:41,556
 OTHER CELLS, SHOWING YOU THE

2141
01:54:41,556 --> 01:54:43,391
 COLON ON THE LOWER RIGHT,

2142
01:54:43,391 --> 01:54:45,593
 APPEARS TO BE RECEPTIVE HERE

2143
01:54:45,593 --> 01:54:46,828
 AS WELL.

2144
01:54:46,828 --> 01:54:53,368
 SO THIS MAY BE EASIER TO DO A 

2145
01:54:53,368 --> 01:54:58,506
 HEAD TO HEAD COMPARISON 

2146
01:54:58,506 --> 01:55:05,880
 BETWEEN THE ILC2'S SO WE WENT 

2147
01:55:05,880 --> 01:55:08,649
 TO THE AMPHIREGULIN LIGAND, A

2148
01:55:08,649 --> 01:55:12,453
 MEMBER OF A LARGE FAMILY AND 

2149
01:55:12,453 --> 01:55:16,057
 WE KNOW ILC2'S ARE NOT THE

2150
01:55:16,057 --> 01:55:23,431
 ONLY PRODUCERS FOR

2151
01:55:23,431 --> 01:55:33,975
 AMPHIREGULIN AND MANY TISSUE

2152
01:55:34,242 --> 01:55:35,676
 T-REGS ARE HIGH FOR

2153
01:55:35,676 --> 01:55:36,144
 EXPRESSION.

2154
01:55:36,144 --> 01:55:39,180
 SO IT IS INTERESTING WE CAN GO

2155
01:55:39,180 --> 01:55:43,418
 BACK WITH THIS SELECTIVE THING

2156
01:55:43,418 --> 01:55:53,928
 THAT EXISTS IS THERE ANY 

2157
01:55:54,495 --> 01:55:57,432
 ADAPTIVE AND COMPARATIVE

2158
01:55:57,432 --> 01:55:58,566
 MODELS.

2159
01:55:58,566 --> 01:56:09,110
 SO WE LOOK AT THE AREG WITH 

2160
01:56:10,778 --> 01:56:17,585
 THE TRICHURIS MURIA INFECTION,

2161
01:56:17,585 --> 01:56:24,258
 THERE IS TARGETED DELEASE OF 

2162
01:56:24,258 --> 01:56:25,460
 AREG IN ILC2'S.

2163
01:56:25,460 --> 01:56:31,599
 HERE WE SHOW THE PROXIMAL

2164
01:56:31,599 --> 01:56:34,769
 COLON GOBLET CELL AND THIS

2165
01:56:34,769 --> 01:56:36,471
 HISTOLOGY TELLS THE STORY THAT

2166
01:56:36,471 --> 01:56:38,306
 THE CYTOKINE RESPONSE IS

2167
01:56:38,306 --> 01:56:43,644
 ALMOST COMPLETELY GONE AND THE

2168
01:56:43,644 --> 01:56:44,812
 ILC2 SPECIFIC REGULATION AND

2169
01:56:44,812 --> 01:56:48,883
 THOSE ANIMALS HAVE A DEFECT IN

2170
01:56:48,883 --> 01:56:54,021
 THEIR BIOLOGY TO EXPRESS THIS

2171
01:56:54,021 --> 01:56:54,555
 PARTICULAR PARASITE.

2172
01:56:54,555 --> 01:56:57,792
 SO GOING BACK TO DSS FOR A

2173
01:56:57,792 --> 01:57:02,463
 SECOND, WE ALSO SEE THE NMU IN

2174
01:57:02,463 --> 01:57:04,165
 THE COLON TISSUE AND THIS

2175
01:57:04,165 --> 01:57:14,709
 APPEARS TO BE A RESPONSE TO

2176
01:57:25,853 --> 01:57:27,355
 AREGULATE INFECTION.

2177
01:57:27,355 --> 01:57:32,627
 HERE WE GAVE THE MICE

2178
01:57:32,627 --> 01:57:33,694
 AMPHIREGULIN IN TYPE 2

2179
01:57:33,694 --> 01:57:36,397
 IMMUNITY AND YOU CAN SEE IT

2180
01:57:36,397 --> 01:57:38,332
 AFFECTS ALMOST ALL OF THEM

2181
01:57:38,332 --> 01:57:40,234
 WITHIN 24 HOURS.

2182
01:57:40,234 --> 01:57:44,772
 SO WHAT HAPPENS IN THE CONTEXT

2183
01:57:44,772 --> 01:57:49,076
 OF DAMAGE SOBERRIVE WITH THAT,

2184
01:57:49,076 --> 01:57:55,316
 YOU SEE WEIGHT LOSS AND OTHER

2185
01:57:55,316 --> 01:58:04,225
 SYMPTOMS, AND ON THE RIGHT, 

2186
01:58:04,225 --> 01:58:06,060
 YOU CAN SEE THE WEIGHT LOSS

2187
01:58:06,060 --> 01:58:13,167
 AND THIS TELLS THE WHOLE STORY

2188
01:58:13,167 --> 01:58:15,736
 HERE. 

2189
01:58:15,736 --> 01:58:21,842
 SO IS THAT DAMAGE A RESULT OF

2190
01:58:21,842 --> 01:58:26,247
 THE AREG FOR THE ILC2.

2191
01:58:26,247 --> 01:58:30,518
 SO IF WE GET THE WILD TYPES

2192
01:58:30,518 --> 01:58:31,719
 THERAPEUTIC NMU, YOU CAN SEE

2193
01:58:31,719 --> 01:58:34,655
 THERE IS A RESTORATION OF THE

2194
01:58:34,655 --> 01:58:35,823
 EPITHELIAL BARRIER TENDENCY

2195
01:58:35,823 --> 01:58:38,292
 AND OVER ON THE FAR RIGHT,

2196
01:58:38,292 --> 01:58:40,228
 THAT MEDIATED TISSUE IS ABSENT

2197
01:58:40,228 --> 01:58:48,102
 AND THE ABSENCE OF ILC2

2198
01:58:48,102 --> 01:58:52,306
 DERIVED AREGULIN SO THIS SHOWS

2199
01:58:52,306 --> 01:59:01,882
 THE NEURON DERIVED DRIVING A 

2200
01:59:01,882 --> 01:59:03,651
 TISSUE CELL AREGULA.

2201
01:59:03,651 --> 01:59:06,921
 IT IS MAKING A FAIR AMOUNT OF

2202
01:59:06,921 --> 01:59:07,888
 AREGULA BUT IT IS SOMETHING

2203
01:59:07,888 --> 01:59:09,357
 ABOUT THE ENVIRONMENT THAT

2204
01:59:09,357 --> 01:59:11,058
 AFFORDS THEM A TISSUE

2205
01:59:11,058 --> 01:59:12,994
 PROTECTIVE FUNCTION THAT

2206
01:59:12,994 --> 01:59:20,334
 CANNOT BE COMPENSATED FOR BY

2207
01:59:20,334 --> 01:59:23,537
 ADAPTIVE LINKEDINO --

2208
01:59:23,537 --> 01:59:23,938
 LYMPHOCYTES.

2209
01:59:23,938 --> 01:59:26,040
 SO LOOKING AT THE PATIENT,

2210
01:59:26,040 --> 01:59:29,644
 THIS IS A LIVE TISSUE BANK AT

2211
01:59:29,644 --> 01:59:30,778
 CORNELL, WE GET LIVE TISSUES

2212
01:59:30,778 --> 01:59:37,118
 EVERY DAY AND YOU SEE ENOUGH 

2213
01:59:37,118 --> 01:59:38,753
 WHERE THE CHOLINERGIC NERVES

2214
01:59:38,753 --> 01:59:42,423
 ARE CAN A ACTIVATED, THESE ARE

2215
01:59:42,423 --> 01:59:44,725
 PATIENTS WITH ACTIVE DISEASE,

2216
01:59:44,725 --> 01:59:48,663
 NOT IN REMISSION AND THEN YOU

2217
01:59:48,663 --> 01:59:56,771
 CAN SEE WHERE WE ACTIVATE THEM

2218
01:59:56,771 --> 02:00:01,575
 AND THE ILC2 ALSO PRODUCES

2219
02:00:01,575 --> 02:00:01,942
 AREGULIN.

2220
02:00:01,942 --> 02:00:04,378
 SO IN THE LAST MINUTE OR TWO I

2221
02:00:04,378 --> 02:00:07,081
 WILL SWITCH TO OTHER STUDIES

2222
02:00:07,081 --> 02:00:09,150
 IN THE CONTEXT OF THE KNOW

2223
02:00:09,150 --> 02:00:11,352
 RESEVENTH TORSION OR PAIN

2224
02:00:11,352 --> 02:00:13,621
 RECEPTOR FAMILY.

2225
02:00:13,621 --> 02:00:17,825
 AND AS YOU KNOW THIS WAS A

2226
02:00:17,825 --> 02:00:19,493
 NOBEL PRIZE A COUPLE OF YEARS

2227
02:00:19,493 --> 02:00:20,328
 AGO.

2228
02:00:20,328 --> 02:00:22,930
 I AM AN IMFOLLOW GIFT AND WE

2229
02:00:22,930 --> 02:00:28,769
 THINK ABOUT WHAT IS IN TISSUE

2230
02:00:28,769 --> 02:00:34,942
 PROTECTION, WHETHER IT BE

2231
02:00:34,942 --> 02:00:35,976
 ITCHING, PSORIASIS, PATIENTS

2232
02:00:35,976 --> 02:00:38,913
 DON'T COMPLAIN ABOUT ON

2233
02:00:38,913 --> 02:00:40,314
 CYTOKINE STORM.

2234
02:00:40,314 --> 02:00:42,583
 PATIENTS WITH CHRONIC

2235
02:00:42,583 --> 02:00:43,551
 INFLAMMATION COMPLAIN ABOUT

2236
02:00:43,551 --> 02:00:44,385
 PAIN.

2237
02:00:44,385 --> 02:00:46,153
 THAT IS THE SYSTEM TOM.

2238
02:00:46,153 --> 02:00:50,558
 SO THERE MUST BE SOME

2239
02:00:50,558 --> 02:00:51,225
 COMMUNICATION BETWEEN THESE

2240
02:00:51,225 --> 02:00:54,128
 IMMUNE COMPLEX THAT RESULT IN

2241
02:00:54,128 --> 02:00:57,865
 THAT PAIN PHENOTYPE AND CAUSES

2242
02:00:57,865 --> 02:01:03,437
 A BUNCH OF INFLAMMATORY

2243
02:01:03,437 --> 02:01:03,804
 DISEASES.

2244
02:01:03,804 --> 02:01:07,074
 SO ANOTHER COMPETENT POST-DOC

2245
02:01:07,074 --> 02:01:17,651
 IN THE LAB LOOKING AT THE GUT

2246
02:01:21,555 --> 02:01:24,692
 INFLAMMATION AND THE PRESENCE

2247
02:01:24,692 --> 02:01:27,995
 OF ILC2'S IN A HEALTHY GUT

2248
02:01:27,995 --> 02:01:29,196
 VERSUS ONE WITH INFLAMMATION

2249
02:01:29,196 --> 02:01:31,065
 SO THIS IS A HEALTHY GUT AND

2250
02:01:31,065 --> 02:01:33,701
 YOU CAN SEE A REMARKABLE

2251
02:01:33,701 --> 02:01:36,070
 CHANGE IN THE INNERVATION IN

2252
02:01:36,070 --> 02:01:41,375
 THE CONTEXT OF THIS ACTIVE

2253
02:01:41,375 --> 02:01:42,209
 INFLAMMATORY DISEASE.

2254
02:01:42,209 --> 02:01:44,512
 AND THEN WE ASK WHAT, IF

2255
02:01:44,512 --> 02:01:47,815
 ANYTHING, IS THE CAUSE OF

2256
02:01:47,815 --> 02:01:53,387
 SENSE SENSATION OF PAIN AND

2257
02:01:53,387 --> 02:01:56,123
 MICROBIOSA AND I WILL SHOW YOU

2258
02:01:56,123 --> 02:02:00,327
 THERE ARE MANY TOOLS WE CAN

2259
02:02:00,327 --> 02:02:06,734
 USE TO ACTIVATE THE NEURONS,

2260
02:02:06,734 --> 02:02:11,172
 OR DELETE NEURONS AND HERE WE

2261
02:02:11,172 --> 02:02:12,339
 CAN SILENCE THE NEURONS AND

2262
02:02:12,339 --> 02:02:16,677
 YOU SEE THE ANIMALS GET A LOT

2263
02:02:16,677 --> 02:02:17,745
 SICKER, GETTING NOTABLY WORSE.

2264
02:02:17,745 --> 02:02:20,414
 SO WE ARE NOT CHANGING THEIR

2265
02:02:20,414 --> 02:02:23,050
 IMMUNE SYSTEM, JUST THE

2266
02:02:23,050 --> 02:02:29,390
 INNERVATION, WE CHANGE THE

2267
02:02:29,390 --> 02:02:33,060
 COMPONENTS OF THE MICROBIOTA

2268
02:02:33,060 --> 02:02:35,496
 AND THEN YOU CAN LOOK AT THE

2269
02:02:35,496 --> 02:02:42,603
 CARTOON THAT THERE IS A

2270
02:02:42,603 --> 02:02:43,671
 TRANSMISSIBLE TRANSBIOSIS

2271
02:02:43,671 --> 02:02:45,439
 ELICITED WHEN WE DELETE THE

2272
02:02:45,439 --> 02:02:47,875
 NEURONS IN THE GUT AND THAT IS

2273
02:02:47,875 --> 02:02:50,010
 AN IMPORTANT DRIVER OF THE

2274
02:02:50,010 --> 02:02:50,678
 INFLAMMATION.

2275
02:02:50,678 --> 02:02:54,048
 SO I WANT TO PRESENT SOME WORK

2276
02:02:54,048 --> 02:03:01,822
 WE'RE DOING IN NUTRITION AND I

2277
02:03:01,822 --> 02:03:05,259
 WILL TAKE JUST A SECOND TO

2278
02:03:05,259 --> 02:03:06,827
 INTRODUCE ANOTHER IMPORTANT

2279
02:03:06,827 --> 02:03:09,563
 PERSON IN THE LAB, ANTOINE

2280
02:03:09,563 --> 02:03:13,467
 GUZMAN WHO HAS BEEN STUDYING

2281
02:03:13,467 --> 02:03:16,570
 TIE VET -- DIET AND A SYSTEM

2282
02:03:16,570 --> 02:03:18,772
 WHERE WE CAN SELECT CHANGES IN

2283
02:03:18,772 --> 02:03:25,045
 THE DIET AND HOW THAT CHANGES

2284
02:03:25,045 --> 02:03:28,415
 THE MICROBIOTA, THE

2285
02:03:28,415 --> 02:03:30,851
 METABOLITES AND HOW THOSE ARE

2286
02:03:30,851 --> 02:03:32,052
 SHOWING IMMUNE RESPONSES.

2287
02:03:32,052 --> 02:03:36,991
 A VERY NICE PAPER PUBLISHED

2288
02:03:36,991 --> 02:03:39,193
 NOT LONG AGO THAT ONE

2289
02:03:39,193 --> 02:03:40,227
 PARTICULAR FIBER, NOT ALL

2290
02:03:40,227 --> 02:03:42,696
 FIBERS ARE THE SAME BUT

2291
02:03:42,696 --> 02:03:45,165
 INNULIN FIBER IS A VERY

2292
02:03:45,165 --> 02:03:54,575
 IMPORTANT DRIVER OF PART 2

2293
02:03:54,575 --> 02:03:56,277
 INFLAMMATION, MICROBIOTIC

2294
02:03:56,277 --> 02:03:58,012
 DEPENDENT, SPECIFICALLY

2295
02:03:58,012 --> 02:04:08,522
 DEPENDENT ON FOLIC ACID AND

2296
02:04:08,522 --> 02:04:10,858
 THERE'S CRISPR TARGETING, A

2297
02:04:10,858 --> 02:04:13,460
 SINGLE ENZYME ENCODED IN A

2298
02:04:13,460 --> 02:04:15,362
 SINGLE BACTERIAL SPECIES THAT

2299
02:04:15,362 --> 02:04:19,633
 IS IMPORTANT IN MEDIATING THIS

2300
02:04:19,633 --> 02:04:21,869
 DIET INDUCED INFLAMMATORY

2301
02:04:21,869 --> 02:04:23,604
 RESPONSE SO HAVING THESE ALL

2302
02:04:23,604 --> 02:04:25,272
 IN ONE STUDY WILL BE VERY

2303
02:04:25,272 --> 02:04:27,608
 POWERFUL AS WE THINK ABOUT HOW

2304
02:04:27,608 --> 02:04:29,276
 TO HARNESS DIET AND NUTRITION,

2305
02:04:29,276 --> 02:04:31,879
 WHETHER IT IS IN THE CONTEXT

2306
02:04:31,879 --> 02:04:33,280
 OF CANCER TO IMPROVE

2307
02:04:33,280 --> 02:04:37,985
 CHECKPOINT BLOCK CADE OR 

2308
02:04:37,985 --> 02:04:40,387
 INFLAMMATION OR BIOLODGICS FOR

2309
02:04:40,387 --> 02:04:42,356
 INFLAMMATORY DISEASE WHICH ARE

2310
02:04:42,356 --> 02:04:43,724
 ONLY 60 PERCENT EFFICACIOUS

2311
02:04:43,724 --> 02:04:48,529
 AND WHY IS THAT AND IS IT

2312
02:04:48,529 --> 02:04:51,932
 BECAUSE PERHAPS WE CAN TWEAK

2313
02:04:51,932 --> 02:04:55,035
 THAT PERCENTAGE JUST WITH

2314
02:04:55,035 --> 02:04:55,469
 DIET.

2315
02:04:55,469 --> 02:04:57,237
 SO IN THE END THERE, THE THREE

2316
02:04:57,237 --> 02:05:05,579
 PEOPLE I TRIED TO EMPHASIZE,

2317
02:05:05,579 --> 02:05:16,156
 HIROSHI AND OTHERS, THANK OUR

2318
02:05:17,057 --> 02:05:18,158
 FUNDERS AND SPONSORS.

2319
02:05:18,158 --> 02:05:19,259
 >> BEAUTIFUL TALK.

2320
02:05:19,259 --> 02:05:22,396
 I WAS WONDERING SINCE THE

2321
02:05:22,396 --> 02:05:24,665
 AREGULIN IS SAID TO GO HAND IN

2322
02:05:24,665 --> 02:05:28,936
 HAND WITH IL C1, I WAS 

2323
02:05:28,936 --> 02:05:30,237
 WONDERING IF ILC2'S MIGHT

2324
02:05:30,237 --> 02:05:33,474
 PRODUCE ALL THE SPONSORING S-R

2325
02:05:33,474 --> 02:05:36,043
 IF THIS IS ONLY WITH RESPECT

2326
02:05:36,043 --> 02:05:37,745
 TO T1?

2327
02:05:37,745 --> 02:05:38,245
 >> GREAT QUESTION.

2328
02:05:38,245 --> 02:05:42,983
 SO FAR MOST SYSTEMS THAT

2329
02:05:42,983 --> 02:05:45,219
 PIERCE ILC2'S ARE NOT MAJOR, I

2330
02:05:45,219 --> 02:05:47,988
 THINK THERE ARE INFLAM

2331
02:05:47,988 --> 02:05:49,757
 INFLAMMATORY CIRCUMSTANCES

2332
02:05:49,757 --> 02:05:56,697
 THAT ARE VERY PREDICTIVE WHEN

2333
02:05:56,697 --> 02:05:59,733
 YOU CONSIDER IMPACTS BUT THERE

2334
02:05:59,733 --> 02:06:02,569
 IS SOME FUNCTION WITH THE ILC2

2335
02:06:02,569 --> 02:06:07,808
 AND THE BIGGEST CROSSOVER

2336
02:06:07,808 --> 02:06:11,412
 BETWEEN TRG, PERHAPS THEY

2337
02:06:11,412 --> 02:06:13,514
 SHARE AREGULIN PRODUCTION.

2338
02:06:13,514 --> 02:06:18,585
 IT APPEARS DIFFERENT 

2339
02:06:18,585 --> 02:06:22,656
 LOCALIZATION OF ILC2'S AND

2340
02:06:22,656 --> 02:06:25,192
 TREGS EVEN THOUGH THERE ARE

2341
02:06:25,192 --> 02:06:26,226
 VERY DIFFERENT CONSEQUENCES ON

2342
02:06:26,226 --> 02:06:29,396
 WHAT THE EFFECTS ARE.

2343
02:06:29,396 --> 02:06:30,564
 >> THANK YOU.

2344
02:06:30,564 --> 02:06:33,400
 >> I AM A POST DOC AND

2345
02:06:33,400 --> 02:06:35,769
 INTERESTED IN WHETHER UNION IS

2346
02:06:35,769 --> 02:06:39,840
 IMPORTANT FOR TREATMENT OR IS 

2347
02:06:39,840 --> 02:06:44,378
 IT THE MMU-R1 THAT IS

2348
02:06:44,378 --> 02:06:46,947
 SOMETHING SECRETING TO BE

2349
02:06:46,947 --> 02:06:47,314
 IMPORTANT.

2350
02:06:47,314 --> 02:06:49,183
 SO WHEN YOU SHOWED IN THE

2351
02:06:49,183 --> 02:06:54,188
 FIRST PART OF YOUR SLIDE WHERE

2352
02:06:54,188 --> 02:06:59,526
 YOU TRANSFERRED THE ILC IN

2353
02:06:59,526 --> 02:07:01,795
 HOST MICE, DOES THE SOURCE OF

2354
02:07:01,795 --> 02:07:02,663
 ILC MATTER?

2355
02:07:02,663 --> 02:07:04,031
 >> THE VERY EARLY
EXPERIMENTS

2356
02:07:04,031 --> 02:07:05,899
 YOU MENTIONED WERE ONES THAT

2357
02:07:05,899 --> 02:07:09,236
 WE DID USING ADOPTIVE TRANSFER

2358
02:07:09,236 --> 02:07:11,171
 AND ALL OF THAT STUFF BECAUSE

2359
02:07:11,171 --> 02:07:14,842
 WE DIDN'T HAVE THE GENETIC

2360
02:07:14,842 --> 02:07:17,978
 TARGETING FOR SELECTIVE 

2361
02:07:17,978 --> 02:07:20,314
 MANIPULATION OF ILC2'S.

2362
02:07:20,314 --> 02:07:22,382
 BUT THE TISSUE PROTECTIVE

2363
02:07:22,382 --> 02:07:24,885
 EFFECTS ARE -- CAN OCCUR

2364
02:07:24,885 --> 02:07:27,321
 BOTH -- I DIDN'T SHOW YOU IN

2365
02:07:27,321 --> 02:07:29,056
 THE INTEREST OF TIME BUT IN

2366
02:07:29,056 --> 02:07:31,158
 THE GUT AND THE SKIN AND

2367
02:07:31,158 --> 02:07:33,460
 USUALLY WHAT WE DO AS A

2368
02:07:33,460 --> 02:07:35,529
 NUMBERS GAME MORE THAN

2369
02:07:35,529 --> 02:07:39,366
 ANYTHING ELSE, ELICIT A LARGE

2370
02:07:39,366 --> 02:07:40,734
 POPULATION OF DONOR TISSUES,

2371
02:07:40,734 --> 02:07:43,604
 TAKE THE DONOR AND ACTIVATE

2372
02:07:43,604 --> 02:07:47,040
 THEM WITH IL33 FOR A COUPLE OF

2373
02:07:47,040 --> 02:07:50,110
 DAYS PRIOR TO INVIVO TRANSFER.

2374
02:07:50,110 --> 02:07:52,379
 SO MOST OF THEM ARE PREACT

2375
02:07:52,379 --> 02:07:53,447
 'SAID THE.

2376
02:07:53,447 --> 02:07:58,218
 MOST OF THEM IN OUR HANDS ARE

2377
02:07:58,218 --> 02:07:58,585
 POSITIVE.

2378
02:07:58,585 --> 02:08:03,590
 THE SYSTEMS WE HAVE WORKED ON

2379
02:08:03,590 --> 02:08:08,562
 SO FAR ARE ALPHAREGULIN DEPEND

2380
02:08:08,562 --> 02:08:13,567
 ENT AND PART OF THE EARLY WORK

2381
02:08:13,567 --> 02:08:20,073
 WAS KNOWN TO BE DEPENDENT WITH

2382
02:08:20,073 --> 02:08:30,551
 ILU SO IT IS KIND OF A CIRCLE.

2383
02:08:30,551 --> 02:08:33,987
 >> GREAT TALK -- DISCERN.

2384
02:08:33,987 --> 02:08:34,721
 [INDISCERNIBLE]

2385
02:08:34,721 --> 02:08:41,929
 YOU SHOWED THE BARRIER CELLS 

2386
02:08:41,929 --> 02:08:43,297
 AND EPITHELIAL FUNCTION, I WAS

2387
02:08:43,297 --> 02:08:44,698
 CURIOUS WHAT SIGNALS THEY ARE

2388
02:08:44,698 --> 02:08:46,867
 GETTING, WHAT THEY ARE SENDING

2389
02:08:46,867 --> 02:08:49,603
 FOR THE TISSUE THEY ARE IN?

2390
02:08:49,603 --> 02:08:50,370
 >> A GREAT QUESTION AND I

2391
02:08:50,370 --> 02:08:51,939
 THINK IF I HAD TIME I WOULD

2392
02:08:51,939 --> 02:08:56,076
 HAVE GIVEN YOU A SNEAK PREVIEW

2393
02:08:56,076 --> 02:08:58,846
 OF SOMEONE WHOSE WORK IS

2394
02:08:58,846 --> 02:09:02,115
 COMING ALONG VERY INTERESTING.

2395
02:09:02,115 --> 02:09:06,220
 CERTAIN WE KNOW EPITHELIAL AND

2396
02:09:06,220 --> 02:09:10,190
 BARRIER SURFACES THROUGH THE 

2397
02:09:10,190 --> 02:09:11,825
 ALARMS OF ILCS AND CYTOKINES

2398
02:09:11,825 --> 02:09:13,827
 ARE VERY IMPORTANT AND WE KNOW

2399
02:09:13,827 --> 02:09:15,462
 INNERVATION IS VERY IMPORTANT

2400
02:09:15,462 --> 02:09:15,863
 AS WELL.

2401
02:09:15,863 --> 02:09:18,832
 I CAN GIVE YOU ONE EXAMPLE BUT

2402
02:09:18,832 --> 02:09:20,100
 THERE ARE MANY, MANY OTHERS.

2403
02:09:20,100 --> 02:09:23,303
 I THINK YOU RAISED THE POINT

2404
02:09:23,303 --> 02:09:26,940
 OF IS THERE A TRIFECTA HERE IN

2405
02:09:26,940 --> 02:09:29,543
 BIOLOGY AND I THINK THE ANSWER

2406
02:09:29,543 --> 02:09:30,777
 IS DEFINITELY YES.

2407
02:09:30,777 --> 02:09:34,882
 AND IT WOULD MAKE SENSE IN --

2408
02:09:34,882 --> 02:09:39,386
 YOU KNOW, I THINK THE IMMUNE

2409
02:09:39,386 --> 02:09:44,725
 SYSTEM IS THE MOST

2410
02:09:44,725 --> 02:09:47,160
 DEVELOPMENTALLY DISTINCT BUT

2411
02:09:47,160 --> 02:09:48,295
 SHARE COMMON FUNCTIONAL

2412
02:09:48,295 --> 02:09:50,497
 TRAITS, SENSE THE INSIDE AND

2413
02:09:50,497 --> 02:09:53,567
 OUTSIDE WORLD, EVOLVE TO FORM

2414
02:09:53,567 --> 02:10:04,144
 COMPLEX SIGNALS AND EVOLVE TO

2415
02:10:06,213 --> 02:10:06,446
 FORM --

2416
02:10:06,446 --> 02:10:06,914
 [INDISCERNIBLE]

2417
02:10:06,914 --> 02:10:11,285
 SO I THINK THAT IS A GREAT

2418
02:10:11,285 --> 02:10:11,818
 QUESTION.

2419
02:10:11,818 --> 02:10:12,219
 >> DAVID --

2420
02:10:12,219 --> 02:10:14,888
 >> YOU ARE STILL YOUNG TO
ME

2421
02:10:14,888 --> 02:10:15,622
 JEFF.

2422
02:10:15,622 --> 02:10:17,357
 >> I HAVE GOT A QUESTION

2423
02:10:17,357 --> 02:10:21,094
 WHETHER THE UNIQUE OR

2424
02:10:21,094 --> 02:10:23,497
 RESOUNDANT FUNCTION OF T

2425
02:10:23,497 --> 02:10:26,066
 CELLS, THE MOST FAIR

2426
02:10:26,066 --> 02:10:33,573
 COMPARISON IS WHEN THEY ARE

2427
02:10:33,573 --> 02:10:35,008
 BOTH PRESENT, BUT YES AT

2428
02:10:35,008 --> 02:10:37,878
 CERTAIN POINT WHEN YOU LOOK AT

2429
02:10:37,878 --> 02:10:41,481
 THE INFECTION, THERE MAY BE NO

2430
02:10:41,481 --> 02:10:45,819
 REDONE DANCE BECAUSE T --

2431
02:10:45,819 --> 02:10:47,788
 REDONE DANCE BECAUSE T CELLS

2432
02:10:47,788 --> 02:10:51,124
 HAVE HAD NO TIME TO WORK ON

2433
02:10:51,124 --> 02:10:51,758
 INFECTION.

2434
02:10:51,758 --> 02:10:58,065
 BUT IS IT FAIR TO SAY THE T 

2435
02:10:58,065 --> 02:11:03,704
 CELLS ARE REDUNDANT BECAUSE

2436
02:11:03,704 --> 02:11:06,340
 ILC CELLS MAY EXPERIENCE DELAY

2437
02:11:06,340 --> 02:11:09,977
 AND WORK OVER TIME AND WE HAVE

2438
02:11:09,977 --> 02:11:11,311
 DATA FOR THAT.

2439
02:11:11,311 --> 02:11:12,346
 >> GREAT QUESTION.

2440
02:11:12,346 --> 02:11:15,148
 AN EXPERIMENT CAN BE DONE IN A

2441
02:11:15,148 --> 02:11:20,053
 MUCH MORE RIGOROUS AND

2442
02:11:20,053 --> 02:11:21,888
 CONTROLLED WAY TO EXPRESS THE

2443
02:11:21,888 --> 02:11:24,391
 CONTEXT AND THE ANSWER IS, I

2444
02:11:24,391 --> 02:11:26,159
 CAN GIVE YOU A LONG OR SHORT

2445
02:11:26,159 --> 02:11:27,794
 ANSWER AND THE SHORT ANSWER IS

2446
02:11:27,794 --> 02:11:30,163
 WE DON'T KNOW BUT THE LONG

2447
02:11:30,163 --> 02:11:33,700
 ANSWER IS WITH EXPOSURE AND

2448
02:11:33,700 --> 02:11:36,436
 DEVELOPMENT OF ANTIGEN

2449
02:11:36,436 --> 02:11:38,038
 SPECIFIC TH2 MEMORY CELLS AND

2450
02:11:38,038 --> 02:11:41,341
 THEN USE SOME OF THOSE TO

2451
02:11:41,341 --> 02:11:49,750
 TARGET THE PRESENCE OF AN 

2452
02:11:49,750 --> 02:11:51,718
 ESTABLISHED T CELL POPULATION

2453
02:11:51,718 --> 02:11:54,921
 AND ARE THEY REDUNDANT.

2454
02:11:54,921 --> 02:11:57,090
 PERHAPS IT IS YES, PERHAPS IT

2455
02:11:57,090 --> 02:11:59,292
 IS NO, PERHAPS IT COMES BACK

2456
02:11:59,292 --> 02:12:01,495
 TO THE TISSUE THEY ARE IN,

2457
02:12:01,495 --> 02:12:03,163
 CERTAINLY A GREAT EXPERIMENT

2458
02:12:03,163 --> 02:12:09,369
 BUT HAVEN'T DONE IT.

2459
02:12:09,369 --> 02:12:12,739
 >> THANK YOU SO MUCH FOR
THE

2460
02:12:12,739 --> 02:12:13,774
 FASCINATING TALK.

2461
02:12:13,774 --> 02:12:16,343
 I WAS STUCK ON THE FIRST SLIDE

2462
02:12:16,343 --> 02:12:17,677
 AND THOUGHT IT SHED QUESTIONS

2463
02:12:17,677 --> 02:12:18,879
 ON THE REST OF IT.

2464
02:12:18,879 --> 02:12:22,215
 I WAS SHOCKED BY THE AMOUNT OF

2465
02:12:22,215 --> 02:12:23,650
 TRANSCRIPTIONAL DIVERSITY

2466
02:12:23,650 --> 02:12:27,888
 BETWEEN THE ILC POPULATIONS

2467
02:12:27,888 --> 02:12:31,825
 INCLUDING DEFINING LINEAGE AND

2468
02:12:31,825 --> 02:12:32,392
 TRANSCRIPTOR FACTORS.

2469
02:12:32,392 --> 02:12:35,929
 SO ONE OF THE QUESTIONS IS TO

2470
02:12:35,929 --> 02:12:39,466
 WHAT EXTENT IS INVOLVED WITH 

2471
02:12:39,466 --> 02:12:41,468
 FUNCTION OF IL22 SEPARATELY IN

2472
02:12:41,468 --> 02:12:44,171
 INDIVIDUAL TISSUE, ARE THEY

2473
02:12:44,171 --> 02:12:45,739
 REALLY THE SAME CELL TYPES AT

2474
02:12:45,739 --> 02:12:51,978
 ALL OR IS THAT A REFLATION OF

2475
02:12:51,978 --> 02:12:54,614
 THE DIFFERENT CELLS AND

2476
02:12:54,614 --> 02:12:55,282
 DIFFERENT TYPES.

2477
02:12:55,282 --> 02:12:58,285
 IS THE RECEPTOR PHYSICALLY

2478
02:12:58,285 --> 02:13:00,220
 USED BY ILC2 AT OTHER SITES?

2479
02:13:00,220 --> 02:13:02,289
 >> THAT IS A GREAT
QUESTION.

2480
02:13:02,289 --> 02:13:07,761
 AND I THINK THE TISSUE

2481
02:13:07,761 --> 02:13:08,895
 SPECIFICITY OF ENRICHMENT OF

2482
02:13:08,895 --> 02:13:10,864
 GENES IS INTERESTING BECAUSE

2483
02:13:10,864 --> 02:13:14,134
 IT TELLS US THAT ALTHOUGH

2484
02:13:14,134 --> 02:13:16,336
 DERIVED FROM COMMON SELLS,

2485
02:13:16,336 --> 02:13:17,671
 THEY HAVE REMARKABLE

2486
02:13:17,671 --> 02:13:22,342
 PLASTICITY IN TERMS OF SHAPING

2487
02:13:22,342 --> 02:13:23,510
 THEIR PREDOMINANT THAN THE

2488
02:13:23,510 --> 02:13:26,213
 FUNCTION BASED ON THE MICRO

2489
02:13:26,213 --> 02:13:27,080
 ENVIRONMENT THEY FIND

2490
02:13:27,080 --> 02:13:28,014
 THEMSELVES IN.

2491
02:13:28,014 --> 02:13:31,051
 CAN YOU TAKE THE ILC FROM ONE

2492
02:13:31,051 --> 02:13:33,487
 TISSUE AND DELIVER IT EX

2493
02:13:33,487 --> 02:13:34,988
 EXCLUSIVELY TO ANOTHER TISSUE

2494
02:13:34,988 --> 02:13:38,959
 AND ASK IT DOES IT REQUIRE A

2495
02:13:38,959 --> 02:13:40,694
 SECOND SIGNATURE FUNCTION

2496
02:13:40,694 --> 02:13:43,363
 DEPENDING ON THAT IF IT IS

2497
02:13:43,363 --> 02:13:45,398
 THAT, WHETHER A NEW HE IS DENS

2498
02:13:45,398 --> 02:13:47,334
 OR COMMUNITY OR WHATEVER.

2499
02:13:47,334 --> 02:13:48,835
 CERTAINLY SOME OF THESE

2500
02:13:48,835 --> 02:13:50,704
 EXPERIMENTS HAVE BEEN DONE.

2501
02:13:50,704 --> 02:13:51,738
 THEY ARE NOT THE BEST BECAUSE

2502
02:13:51,738 --> 02:13:55,809
 THEY ARE A LITTLE HARD TO

2503
02:13:55,809 --> 02:13:57,277
 INTERPRET AT SOME TIMES BUT

2504
02:13:57,277 --> 02:14:01,481
 THERE APPEAR TO BE SOME

2505
02:14:01,481 --> 02:14:05,752
 ASPECTS THAT APPEAR TO BE AT

2506
02:14:05,752 --> 02:14:08,488
 SOME POINT BUT ANOTHER PART

2507
02:14:08,488 --> 02:14:14,027
 ISN'T RESPOND TO WHERE THEY

2508
02:14:14,027 --> 02:14:15,262
 FIND THEMSELVES.

2509
02:14:15,262 --> 02:14:19,266
 SO THE TISSUES WE SEE THAT THE

2510
02:14:19,266 --> 02:14:27,174
 MOST, ILC2'S ARE THE RECEPTORS

2511
02:14:27,174 --> 02:14:29,609
 OF THE INFLAMMATORY RESPONSE.

2512
02:14:29,609 --> 02:14:32,913
 NOW CAN THEY BE

2513
02:14:32,913 --> 02:14:33,613
 INTERDEPENDENT?

2514
02:14:33,613 --> 02:14:34,014
 ABSOLUTELY.

2515
02:14:34,014 --> 02:14:37,350
 WE HAVEN'T SEEN IT YET BUT I

2516
02:14:37,350 --> 02:14:38,185
 WOULDN'T BE AMAZED IF THAT

2517
02:14:38,185 --> 02:14:39,119
 WERE THE CASE.

2518
02:14:39,119 --> 02:14:40,020
 SO I DON'T THINK THAT IS THE

2519
02:14:40,020 --> 02:14:41,788
 END OF IT, I THINK THAT IS

2520
02:14:41,788 --> 02:14:43,089
 JUST ONE INTERESTING ASPECT.

2521
02:14:43,089 --> 02:14:49,029
 I THINK THAT IS SOMETHING THAT

2522
02:14:49,029 --> 02:14:50,597
 SPOTLIGHTS THE IL-IMMUNE

2523
02:14:50,597 --> 02:14:54,968
 BIOLOGY AND A GOOD ROAD MAP TO

2524
02:14:54,968 --> 02:14:55,769
 INVESTIGATE FURTHER.

2525
02:14:55,769 --> 02:14:59,806
 >> GREAT TALK BUT AS YOU

2526
02:14:59,806 --> 02:15:03,243
 MENTIONED, THE CHRONIC

2527
02:15:03,243 --> 02:15:06,446
 INFLAMMATION IS NOT ABOUT

2528
02:15:06,446 --> 02:15:07,247
 MEDICATION, COMPLAINING ABOUT

2529
02:15:07,247 --> 02:15:17,557
 PAIN, THE FIRST THING WE DO IS

2530
02:15:17,557 --> 02:15:18,058
 TAKE MEDICATIONS.

2531
02:15:18,058 --> 02:15:20,794
 WHAT HAPPENS WHEN YOU TAKE

2532
02:15:20,794 --> 02:15:22,529
 RAND RANDOM PAIN PILLS ONE

2533
02:15:22,529 --> 02:15:23,163
 AFTER ANOTHER?

2534
02:15:23,163 --> 02:15:24,497
 >> I DON'T KNOW THE
ANSWER TO

2535
02:15:24,497 --> 02:15:27,367
 THAT BUT WE HAVE BEEN TALKING

2536
02:15:27,367 --> 02:15:29,536
 ABOUT THIS BECAUSE CERTAINLY

2537
02:15:29,536 --> 02:15:31,438
 MANIPULATION, NOT USE I THINK

2538
02:15:31,438 --> 02:15:36,109
 OVER THE COUNTER PAIN MEDS, AN

2539
02:15:36,109 --> 02:15:37,911
 EASIER EXPERIMENT WE CAN DO AT

2540
02:15:37,911 --> 02:15:40,180
 THE MOMENT BUT WHERE WE CAN

2541
02:15:40,180 --> 02:15:41,748
 ALTER THE STATE OF THE

2542
02:15:41,748 --> 02:15:43,783
 CIRCUITS AND MAP THAT TISSUE

2543
02:15:43,783 --> 02:15:45,318
 TO MICRO ENVIRONMENTS AND WHEN

2544
02:15:45,318 --> 02:15:48,855
 WE DO ALL OF THAT, YOU SEE

2545
02:15:48,855 --> 02:15:50,190
 REMARKABLE CHANGES AND I DON'T

2546
02:15:50,190 --> 02:15:52,959
 HAVE TIME TO SHOW BUT THE

2547
02:15:52,959 --> 02:15:58,932
 COMBINATION COMPETITION OF THE

2548
02:15:58,932 --> 02:16:06,906
 MICROBIOTA AND ALSO IN THE

2549
02:16:06,906 --> 02:16:08,642
 COMPLEX, EVEN ACUTE PAIN

2550
02:16:08,642 --> 02:16:11,611
 KILLERS CAN HAVE A DRAMATIC

2551
02:16:11,611 --> 02:16:13,179
 EFFECT ON T CELL FUNCTION AND

2552
02:16:13,179 --> 02:16:15,115
 I THINK WE DON'T UNDERSTAND IT

2553
02:16:15,115 --> 02:16:16,182
 YET.

2554
02:16:16,182 --> 02:16:16,983
 VERY GOOD POINT.

2555
02:16:16,983 --> 02:16:22,656
 OKAY, THANK YOU.

2556
02:16:22,656 --> 02:16:23,123
 [APPLAUSE]

2557
02:16:23,123 --> 02:16:24,190
 >> I WOULD LIKE TO THANK
ALL

2558
02:16:24,190 --> 02:16:26,326
 THE SPEAKERS FOR THIS VERY

2559
02:16:26,326 --> 02:16:28,261
 EXCITING AND ENGAGING SESSION.

2560
02:16:28,261 --> 02:16:30,463
 PLEASE JOIN US FOR A COFFEE

2561
02:16:30,463 --> 02:16:31,865
 BREAK FOR MORE DISCUSSION AND

2562
02:16:31,865 --> 02:16:35,168
 WE WILL RECONVENE AT

2563
02:16:35,168 --> 02:16:35,568
 11:05 A.M.

2564
02:16:35,568 --> 02:16:37,570
 PLEASE VISIT THE POSTER

2565
02:16:37,570 --> 02:16:40,840
 SECTION TO SUPPORT OUR NIH

2566
02:16:40,840 --> 02:16:42,542
 TRAINEES DURING THE COFFEE

2567
02:16:42,542 --> 02:16:42,552
 BREAK AND THE LUNCH BREAK.
THANK YOU.

2568
02:16:42,552 --> 02:16:44,521
WELCOME BACK, HOPE YOU
HAD

2569
02:16:44,521 --> 02:16:46,423
 A NICE COFFEE AND POSTER

2570
02:16:46,423 --> 02:16:46,956
 SESSION INTERACTION.

2571
02:16:46,956 --> 02:16:49,692
 IT IS MY PLEASURE TO LAUNCH

2572
02:16:49,692 --> 02:16:56,433
 SESSION 5 ON INNATE CELL

2573
02:16:56,433 --> 02:16:57,867
 SIGNALING BY JULIA GRIFFIN WHO

2574
02:16:57,867 --> 02:17:00,570
 IS JOINING US FROM FAR AWAY

2575
02:17:00,570 --> 02:17:04,974
 AND WILL TALK ABOUT DYNAMIC

2576
02:17:04,974 --> 02:17:08,812
 CHANGES AND I THINK THERE ARE

2577
02:17:08,812 --> 02:17:11,681
 SOME COOL VIDEOS.

2578
02:17:11,681 --> 02:17:14,851
 >> OKAY, THANKS VERY
MUCH, A

2579
02:17:14,851 --> 02:17:17,987
 PLEASURE TO JOIN NIH, I WILL

2580
02:17:17,987 --> 02:17:28,531
 START THE TIMER AND MY TALK,

2581
02:17:32,235 --> 02:17:33,970
 THESE ARE NOT ONLY IMPORTANT

2582
02:17:33,970 --> 02:17:37,006
 CELLS IN FIGHTING OFF

2583
02:17:37,006 --> 02:17:39,709
 INFECTION BUT ALSO HAVE

2584
02:17:39,709 --> 02:17:40,643
 INCREDIBLY COOL BIOLOGY

2585
02:17:40,643 --> 02:17:42,345
 OVERLYING IT AND THIS IS WHAT

2586
02:17:42,345 --> 02:17:44,781
 DREW ME INTO STUDYING THE

2587
02:17:44,781 --> 02:17:48,885
 CELLS AND WHAT GOES ON INSIDE

2588
02:17:48,885 --> 02:17:54,324
 THEM IN TERMS OF THE REAT THE

2589
02:17:54,324 --> 02:17:57,994
 PRESENT TIMEOR -- OF THE

2590
02:17:57,994 --> 02:17:58,695
 RECEPTORS.

2591
02:17:58,695 --> 02:18:06,736
 SO THEY ARE MADE UP OF THESE

2592
02:18:06,736 --> 02:18:08,438
 SYNAPSES AND INSIDE THEM THEY

2593
02:18:08,438 --> 02:18:18,882
 HAVE SHE IS SECRETORY 

2594
02:18:19,415 --> 02:18:25,054
 LYSOSOMES CONTAINING PERFORIN

2595
02:18:25,054 --> 02:18:26,356
 AND GRANZYMES.

2596
02:18:26,356 --> 02:18:31,761
 THIS IS AN UNUSUAL AMOUNT OF 

2597
02:18:31,761 --> 02:18:32,795
 TOLL LARRIZING SECRETION.

2598
02:18:32,795 --> 02:18:35,365
 SO YOU SEE THE BACK OF THE

2599
02:18:35,365 --> 02:18:38,768
 CELL WITH AN ACCUMULATION OF

2600
02:18:38,768 --> 02:18:39,903
 TARGETS OFFICIALLY AND THEN

2601
02:18:39,903 --> 02:18:42,472
 YOU WILL SEE IT DEPLETES AND

2602
02:18:42,472 --> 02:18:50,480
 AT THAT POINT, THE CENTROSOME 

2603
02:18:50,480 --> 02:18:59,355
 COMES FORWARD BRINGING THE

2604
02:18:59,355 --> 02:19:02,158
 GRANZYMES WHICH THEN CAN KILL.

2605
02:19:02,158 --> 02:19:09,599
 SO THIS WAS BROUGHT FORWARD AT

2606
02:19:09,599 --> 02:19:11,067
 THE NIH BETWEEN A STUDENT AND

2607
02:19:11,067 --> 02:19:13,836
 MYSELF AND YOU CAN SEE THE

2608
02:19:13,836 --> 02:19:15,705
 BODIES, THIS IS THE ACTIN

2609
02:19:15,705 --> 02:19:24,614
 ACROSS THE CENTER AND THE

2610
02:19:24,614 --> 02:19:26,516
 SECRETORY SIGNALS AND YOU CAN

2611
02:19:26,516 --> 02:19:28,284
 SEE IT GOES POP.

2612
02:19:28,284 --> 02:19:32,722
 IT IS TERMINATED BY A VERY

2613
02:19:32,722 --> 02:19:33,990
 ACTIVE ACTIN RECOVERY AND SO

2614
02:19:33,990 --> 02:19:37,594
 WE WANT TO KNOW HOW DOES IT

2615
02:19:37,594 --> 02:19:37,994
 WORK.

2616
02:19:37,994 --> 02:19:41,030
 SO SOME WORK WE DID IN 2018

2617
02:19:41,030 --> 02:19:42,632
 AND WHAT WE DISCOVERED IS

2618
02:19:42,632 --> 02:19:44,767
 BECAUSE OF THE DYNAMIC

2619
02:19:44,767 --> 02:19:46,002
 MEMBRANE CHANGES, THE

2620
02:19:46,002 --> 02:19:46,903
 COMPOSITION OF THE MEMBRANE

2621
02:19:46,903 --> 02:19:48,738
 CHANGES AND THAT IS WHAT

2622
02:19:48,738 --> 02:19:50,773
 CONTROLS WHETHER THE ACTIN IS

2623
02:19:50,773 --> 02:19:51,808
 THERE OR NOT.

2624
02:19:51,808 --> 02:19:55,645
 AND JUST VERY BRIEFLY, DURING

2625
02:19:55,645 --> 02:20:00,283
 T CELERY SEPTEMBEROR

2626
02:20:00,283 --> 02:20:01,684
 SIGNALING, THERE IS

2627
02:20:01,684 --> 02:20:11,461
 SPECIALIZATION AT THE SYNAPSE 

2628
02:20:11,461 --> 02:20:15,632
 AND THAT GENERATES GLYCEROL SO

2629
02:20:15,632 --> 02:20:20,336
 THERE IS A PARTICULAR MEMBRANE

2630
02:20:20,336 --> 02:20:23,740
 SECRETION REQUIRED TO DEPLETE

2631
02:20:23,740 --> 02:20:24,107
 THE ACTIN.

2632
02:20:24,107 --> 02:20:25,975
 SO THEN WHAT WE LOOKED INTO

2633
02:20:25,975 --> 02:20:30,847
 NEXT IS WHAT HAPPENS AT THE T

2634
02:20:30,847 --> 02:20:37,854
 CELERY SEPTEMBERO -- THE T

2635
02:20:37,854 --> 02:20:43,760
 CELL CE -- RECEPTOR AND YOU

2636
02:20:43,760 --> 02:20:47,363
 CAN SEE THIS PIP 2 HERE

2637
02:20:47,363 --> 02:20:49,232
 RECRUITING THE ACTIN AND IT IS

2638
02:20:49,232 --> 02:20:49,766
 IMMEDIATELY KILLED.

2639
02:20:49,766 --> 02:20:53,403
 SO THERE IS A SEAMLESS

2640
02:20:53,403 --> 02:20:54,837
 RECOGNITION, ACTIVATION AND

2641
02:20:54,837 --> 02:20:56,406
 THEN NEEDS TERMINATION IN

2642
02:20:56,406 --> 02:20:59,842
 ORDER TO RELEASE THE T CELLS

2643
02:20:59,842 --> 02:21:01,744
 SO YOU CAN HAVE SERIAL

2644
02:21:01,744 --> 02:21:02,078
 KILLERS.

2645
02:21:02,078 --> 02:21:04,147
 SO HOW DOES THAT WORK?

2646
02:21:04,147 --> 02:21:06,249
 TO TRY TO UNDERSTAND AT A VERY

2647
02:21:06,249 --> 02:21:09,085
 HIGH RESOLUTION, WE TOOK

2648
02:21:09,085 --> 02:21:14,090
 ADVANTAGE OF A T CELL

2649
02:21:14,090 --> 02:21:16,726
 ACTIVATION AND THAT WAY THE

2650
02:21:16,726 --> 02:21:25,268
 EVENT CAN BE REVEALED BY

2651
02:21:25,268 --> 02:21:26,903
 ELECTRON MICROSCOPY.

2652
02:21:26,903 --> 02:21:30,440
 SO IT ALLOWS TO YOU SEE THE

2653
02:21:30,440 --> 02:21:33,476
 VERY FIRST CONTACT IS MADE

2654
02:21:33,476 --> 02:21:35,845
 FROM THE TINY TIPS WHERE THE T

2655
02:21:35,845 --> 02:21:37,613
 CELLS ARE CONCENTRATED AND

2656
02:21:37,613 --> 02:21:40,116
 THEN YOU CAN SEE IT THEN

2657
02:21:40,116 --> 02:21:45,321
 CLUSTERS INTO WHAT IS KNOWN AS

2658
02:21:45,321 --> 02:21:46,422
 THE SUPER ACTIVATION COMPLEX.

2659
02:21:46,422 --> 02:21:48,091
 THIS IS ALL VERY WELL BUT WE

2660
02:21:48,091 --> 02:21:54,731
 WANT TO SEE THE WHOLE BIG

2661
02:21:54,731 --> 02:21:55,331
 ASSIGNMENT.

2662
02:21:55,331 --> 02:22:00,937
 SO WE BUILT THIS IN 3D UNDER A

2663
02:22:00,937 --> 02:22:01,604
 MICROSCOPE TO CONSTRUCT WHAT

2664
02:22:01,604 --> 02:22:02,538
 IS GOING ON.

2665
02:22:02,538 --> 02:22:09,312
 THIS ALLOWS US A 3 DIMENSIONAL

2666
02:22:09,312 --> 02:22:10,012
 STRUCTURE ACROSS A RESOLUTION

2667
02:22:10,012 --> 02:22:11,781
 AND THIS IS WHAT WE FOUND.

2668
02:22:11,781 --> 02:22:13,950
 THE BOTTOM HERE IS THE T CELL,

2669
02:22:13,950 --> 02:22:15,351
 THIS IS THE TARGET CELL AND

2670
02:22:15,351 --> 02:22:21,390
 YOU CAN SEE THE T CELLS IN A

2671
02:22:21,390 --> 02:22:22,925
 VERY TIGHTEN CLOSED MEMBRANE

2672
02:22:22,925 --> 02:22:26,529
 SO WE LABELED WHERE THERE IS

2673
02:22:26,529 --> 02:22:32,969
 JUST T CELL MEMBRANES AND THEN

2674
02:22:32,969 --> 02:22:36,305
 THE T CELL APEX LABELED IN

2675
02:22:36,305 --> 02:22:36,773
 GREEN.

2676
02:22:36,773 --> 02:22:45,381
 SO WHAT YOU SEE IS NICE 

2677
02:22:45,381 --> 02:22:47,583
 ENDEMIC STRUCTURES FORMING,

2678
02:22:47,583 --> 02:22:51,320
 AND ACTIN IN T CELL AND WHERE

2679
02:22:51,320 --> 02:22:52,755
 IS THE STRUCTURE OF THE T

2680
02:22:52,755 --> 02:22:53,156
 CELLS?

2681
02:22:53,156 --> 02:22:58,494
 IT IS IN THIS MEMBRANE OUTSIDE

2682
02:22:58,494 --> 02:22:59,729
 THE CELL.

2683
02:22:59,729 --> 02:23:08,738
 SO THEY ARE FROM 225 TO 200

2684
02:23:08,738 --> 02:23:12,475
 NANOMETERS AND I LEARNED 

2685
02:23:12,475 --> 02:23:15,111
 IMMUNOLOGY IN THE CELL

2686
02:23:15,111 --> 02:23:16,078
 BIOINSTITUTE AND SO I

2687
02:23:16,078 --> 02:23:17,680
 DESCRIBED THIS TO MY COLLEAGUE

2688
02:23:17,680 --> 02:23:25,354
 AND HE SAID OH, WE CALL THESE

2689
02:23:25,354 --> 02:23:27,490
 ECTOCITES WHICH DESCRIBES THE

2690
02:23:27,490 --> 02:23:29,025
 FREQUENT SHEDDING OF RIGHT

2691
02:23:29,025 --> 02:23:31,761
 SIDE OUT, A PITCHING OUT FROM

2692
02:23:31,761 --> 02:23:33,329
 THE MEMBRANE AND WHAT WAS

2693
02:23:33,329 --> 02:23:35,865
 INTERESTING IS THEY SAW

2694
02:23:35,865 --> 02:23:39,635
 SORTING OF THE MEMBRANE BY

2695
02:23:39,635 --> 02:23:40,636
 THESE T CELLS.

2696
02:23:40,636 --> 02:23:46,909
 SO OF COURSE THESE OUTWARD

2697
02:23:46,909 --> 02:23:50,513
 BUDDING OF THE NEUTRO PHILS

2698
02:23:50,513 --> 02:23:52,281
 WHICH WAS SHOWN A NUMBER OF

2699
02:23:52,281 --> 02:23:54,116
 YEARS AGO, THEY COULD SEE SOME

2700
02:23:54,116 --> 02:23:55,751
 BUDDING BUT IT WAS DIFFICULT

2701
02:23:55,751 --> 02:23:58,354
 TO SEE ON THE SECTION AND THEY

2702
02:23:58,354 --> 02:24:08,865
 WERE JUST USING CORRELATED

2703
02:24:09,832 --> 02:24:11,834
 LIGHT MICROSCOPY WHERE IT IS

2704
02:24:11,834 --> 02:24:13,469
 NOT VERY CLEAR.

2705
02:24:13,469 --> 02:24:16,639
 SO WHAT THIS SIGNALS IS THE T

2706
02:24:16,639 --> 02:24:18,107
 CELLS ARE ACTIVATING OTHER

2707
02:24:18,107 --> 02:24:20,209
 CELLS AND THEY THOUGHT THIS

2708
02:24:20,209 --> 02:24:29,318
 WAS A MECHANISM FOUND IN DOWN

2709
02:24:29,318 --> 02:24:29,785
 REGULATION.

2710
02:24:29,785 --> 02:24:32,889
 AND THEY ALSO THOUGHT THE T

2711
02:24:32,889 --> 02:24:35,191
 CELLS ARE NOT ACTIVATED

2712
02:24:35,191 --> 02:24:39,562
 BECAUSE THEY WERE DEVOID OF

2713
02:24:39,562 --> 02:24:40,029
 PHOSPHORYLATION.

2714
02:24:40,029 --> 02:24:41,430
 SO THESE WERE THE CONCLUSIONS

2715
02:24:41,430 --> 02:24:43,099
 AT THE TIME BECAUSE IT FITTED

2716
02:24:43,099 --> 02:24:45,701
 WITH WHAT WE THOUGHT WE KNEW

2717
02:24:45,701 --> 02:24:50,806
 ABOUT THE T CELL DOWN

2718
02:24:50,806 --> 02:24:52,508
 REGULATION WHERE IT GOES

2719
02:24:52,508 --> 02:24:54,043
 ACROSS THE MEMBRANE AND

2720
02:24:54,043 --> 02:25:00,383
 THOUGHT TO UNDERGO ACTIVATION

2721
02:25:00,383 --> 02:25:01,217
 END OCYTOSIS --

2722
02:25:01,217 --> 02:25:01,851
 [INDISCERNIBLE]

2723
02:25:01,851 --> 02:25:03,986
 SO WHEN WE LOOKED AT OUR

2724
02:25:03,986 --> 02:25:05,922
 IMAGES, WE COULD SEE THAT YES

2725
02:25:05,922 --> 02:25:12,161
 INDEED WE COULD SEE THE

2726
02:25:12,161 --> 02:25:14,330
 ENDOCYTOSIS, THE FACTOR AT THE

2727
02:25:14,330 --> 02:25:19,368
 BOTTOM AND THE ECTOCYTOSIS.

2728
02:25:19,368 --> 02:25:21,337
 SO THROUGH A LOT OF WORK, WE

2729
02:25:21,337 --> 02:25:31,914
 THOUGHT THERE ARE NOT MA MANY

2730
02:25:35,351 --> 02:25:35,851
 ENDOCYTOSIS STRUCTURES.

2731
02:25:35,851 --> 02:25:38,454
 SO A GOOD FRIEND AND COLLEAGUE

2732
02:25:38,454 --> 02:25:44,460
 RIGHT DOWN THE STAIRS FROM ME,

2733
02:25:44,460 --> 02:25:50,900
 DAVID AHERN HAS DONE ENORMOUS

2734
02:25:50,900 --> 02:25:54,870
 ECTOCYTOSIS AND END OCYTOSIS

2735
02:25:54,870 --> 02:26:01,577
 WORK AND WHAT HE HAS SHOWN IS

2736
02:26:01,577 --> 02:26:05,915
 IT IS THIS MOTIF THAT ALLOWS

2737
02:26:05,915 --> 02:26:09,518
 IT TO BE EXPOSED AND WHERE YOU

2738
02:26:09,518 --> 02:26:14,290
 GOT T CELL ACTIN REGULATION,

2739
02:26:14,290 --> 02:26:19,962
 THERE IS VERY LITTLE T CELL

2740
02:26:19,962 --> 02:26:20,363
 ACTIVATION.

2741
02:26:20,363 --> 02:26:24,166
 SO WHAT THIS MEANS, I DON'T

2742
02:26:24,166 --> 02:26:24,734
 KNOW.

2743
02:26:24,734 --> 02:26:30,172
 SO WHAT THIS SHOWS, THERE IS

2744
02:26:30,172 --> 02:26:34,510
 ACTIN REGULATION BUT YOU ARE

2745
02:26:34,510 --> 02:26:38,748
 NOT GETTING THE ENDOCYTOSIS.

2746
02:26:38,748 --> 02:26:46,689
 SO WHAT IS ENDOC --

2747
02:26:46,689 --> 02:26:47,656
 ECTOCYTOSIS?

2748
02:26:47,656 --> 02:26:49,925
 THIS WILL SHED THE T CELERY

2749
02:26:49,925 --> 02:26:51,927
 SEPTEMBER TORE AND THEY ALL

2750
02:26:51,927 --> 02:26:54,330
 SHED ON THIS VERY TINY PATCH

2751
02:26:54,330 --> 02:26:57,299
 ON THE MEMBRANE HERE AND WE

2752
02:26:57,299 --> 02:27:00,469
 SAW MORE AS WE GET MORE AND

2753
02:27:00,469 --> 02:27:01,170
 MORE TINY PATCHES.

2754
02:27:01,170 --> 02:27:02,371
 AND THE OTHER THING WE FOUND

2755
02:27:02,371 --> 02:27:12,381
 IS AS THE ECTOCYTES ARE

2756
02:27:12,381 --> 02:27:15,551
 DETACHED, THERE IS A BINDING

2757
02:27:15,551 --> 02:27:16,619
 THAT APPEARS TO BE GOING ON

2758
02:27:16,619 --> 02:27:18,888
 AND AS THEY SHED, THEY PULL

2759
02:27:18,888 --> 02:27:21,457
 OFF AND YOU GET AN AREA OF

2760
02:27:21,457 --> 02:27:21,857
 SEPARATION.

2761
02:27:21,857 --> 02:27:23,059
 THIS ENABLES THE T CELLS TO

2762
02:27:23,059 --> 02:27:27,997
 LET GO OF THE TARGET AND MOVE

2763
02:27:27,997 --> 02:27:29,231
 ON TO SKILLING SO WE THINK

2764
02:27:29,231 --> 02:27:30,633
 THAT IS THE IMPORTANT ROLE.

2765
02:27:30,633 --> 02:27:32,234
 HOW DOES THAT WORK?

2766
02:27:32,234 --> 02:27:36,338
 IN THE EARLIER PAPER, Dr.

2767
02:27:36,338 --> 02:27:39,708
 JACKSON SUGGESTED IT IS REALLY

2768
02:27:39,708 --> 02:27:44,046
 LIKE A VIRAL BUDDING AND THE

2769
02:27:44,046 --> 02:27:45,481
 ECTOCYTES INVOLVED IN THAT

2770
02:27:45,481 --> 02:27:46,982
 BUDDING AND THIS COULD BE THE

2771
02:27:46,982 --> 02:27:49,485
 SAME THING THAT IS HAPPENING

2772
02:27:49,485 --> 02:27:52,455
 WITH THE T CELERY SEPTEMBER

2773
02:27:52,455 --> 02:27:58,961
 TORE COMING OUT IN VIVO.

2774
02:27:58,961 --> 02:28:03,966
 BUT ACTUALLY AS PREVIOUSLY 

2775
02:28:03,966 --> 02:28:06,569
 REPORTED IN ECTOCYTOSIS, IT

2776
02:28:06,569 --> 02:28:11,841
 MESSES UP THE SYNAPSE AND IS

2777
02:28:11,841 --> 02:28:13,209
 COMPLICATED SO THAT IS WHY

2778
02:28:13,209 --> 02:28:13,676
 NOTHING HAPPENS.

2779
02:28:13,676 --> 02:28:15,177
 SO IT IS AN OPEN QUESTION.

2780
02:28:15,177 --> 02:28:17,146
 WE DON'T KNOW EXACTLY THE

2781
02:28:17,146 --> 02:28:18,881
 MATRIX AND THAT IS ONE OF THE

2782
02:28:18,881 --> 02:28:20,182
 THINGS WE'RE LOOKING INTO NOW.

2783
02:28:20,182 --> 02:28:27,756
 SO WHAT HAPPENS THEN TO THE T

2784
02:28:27,756 --> 02:28:37,333
 CELERY SEPTEMBEROR --

2785
02:28:37,333 --> 02:28:39,168
 RECEPTOR ECTODERMS THAT ARE

2786
02:28:39,168 --> 02:28:39,468
 SHED?

2787
02:28:39,468 --> 02:28:42,138
 YOU CAN SEE HERE THEY ARE

2788
02:28:42,138 --> 02:28:52,681
 INTERNALIZED AND TAKEN INTO 

2789
02:28:53,082 --> 02:28:54,016
 THE TARGET CELLS.

2790
02:28:54,016 --> 02:28:55,851
 SO HERE YOU CAN SEE IT IS

2791
02:28:55,851 --> 02:28:57,319
 OCCURRING, TAKEN INTO THE

2792
02:28:57,319 --> 02:28:59,655
 TARGET CELLS AND OVER TIME IS

2793
02:28:59,655 --> 02:29:00,823
 KILLING IT.

2794
02:29:00,823 --> 02:29:02,925
 SO THE SAYING EAT MY DIRT

2795
02:29:02,925 --> 02:29:04,994
 COULD BE THE RESPONSE FROM THE

2796
02:29:04,994 --> 02:29:06,662
 T CELL BUT ESSENTIALLY IT IS A

2797
02:29:06,662 --> 02:29:11,467
 VERY CLEVER WAY OF GETTING RID

2798
02:29:11,467 --> 02:29:13,602
 OF YOUR ECTOSOMES. 

2799
02:29:13,602 --> 02:29:18,507
 SO THE PRIME TARGETS ARE THE

2800
02:29:18,507 --> 02:29:20,509
 ECTOSOMES THEMSELVES AND SO

2801
02:29:20,509 --> 02:29:23,746
 WHERE DID THIS IDEA COME FROM 

2802
02:29:23,746 --> 02:29:34,290
 THAT THE T CELL RECEPTOR IS

2803
02:29:34,490 --> 02:29:34,690
 LOST?

2804
02:29:34,690 --> 02:29:38,027
 THERE IS A PAPER THAT SHOWS IT

2805
02:29:38,027 --> 02:29:40,629
 IS LOST AS CALCIUM INCREASES

2806
02:29:40,629 --> 02:29:44,934
 AND IS DEPEND ENT ON A SIGNAL.

2807
02:29:44,934 --> 02:29:50,673
 SO WE LOOKED AT THE

2808
02:29:50,673 --> 02:29:56,712
 ECTOCYTOSIS, LOOKING FOR A

2809
02:29:56,712 --> 02:29:59,615
 SIGNAL AND YOU CAN SEE IT

2810
02:29:59,615 --> 02:30:08,657
 INCREASES WITH THE SIGNAL AND 

2811
02:30:08,657 --> 02:30:14,663
 HAS THE TCELL RECEPTOR

2812
02:30:14,663 --> 02:30:20,169
 DECREASES AND THE ECTOCYTOSIS

2813
02:30:20,169 --> 02:30:20,836
 INCREASES.

2814
02:30:20,836 --> 02:30:21,971
 SO HOW CAN THIS BE?

2815
02:30:21,971 --> 02:30:25,441
 YOU CAN SEE LOTS OF T CELLS

2816
02:30:25,441 --> 02:30:31,680
 AND WHERE YOU HAVE A STRONG 

2817
02:30:31,680 --> 02:30:32,648
 SIGNAL, THE ECTOCYTOSIS IS

2818
02:30:32,648 --> 02:30:37,119
 HERE, THEY ARE ALL

2819
02:30:37,119 --> 02:30:39,755
 INTERNALIZED. 

2820
02:30:39,755 --> 02:30:46,161
 SO T CELLS OUTSIDE WHERE THE

2821
02:30:46,161 --> 02:30:51,600
 CELLS ARE PRESENT BUT THE 

2822
02:30:51,600 --> 02:30:52,968
 SYNAPSE IS ECTOCYTOSED.

2823
02:30:52,968 --> 02:30:56,105
 SO I CAN'T SAY HOW THAT MAKES

2824
02:30:56,105 --> 02:30:57,239
 ANY SENSE, THAT IS AN

2825
02:30:57,239 --> 02:30:58,340
 INTERESTING QUESTION BUT I CAN

2826
02:30:58,340 --> 02:30:59,375
 TELL YOU WHY IT WOULD MAKE

2827
02:30:59,375 --> 02:31:00,909
 SENSE AND THAT IS BECAUSE WHEN

2828
02:31:00,909 --> 02:31:04,480
 YOU NEED TO DELIVER MORE T

2829
02:31:04,480 --> 02:31:07,449
 CELLS, YOU HAVE LOT OFF YOUR

2830
02:31:07,449 --> 02:31:12,554
 TCR, SHED IN ECTOCYTOSIS AND

2831
02:31:12,554 --> 02:31:21,597
 THEN WHEN YOU NEED MORE, THE

2832
02:31:21,597 --> 02:31:22,598
 ENDOCYTOSIS CLUSTERS WITHIN

2833
02:31:22,598 --> 02:31:24,133
 THREE MINUTES OF CONTACT AND

2834
02:31:24,133 --> 02:31:26,368
 THAT IS BEING CLUSTED JUST

2835
02:31:26,368 --> 02:31:27,836
 WITHIN THE SURFACE BUT THEN

2836
02:31:27,836 --> 02:31:31,173
 YOU SEE THE POOLS OF TCRS ARE

2837
02:31:31,173 --> 02:31:35,444
 DELIVERED LATER SO THEY ARE

2838
02:31:35,444 --> 02:31:36,578
 REPLENISHED FROM THE VEHICLE

2839
02:31:36,578 --> 02:31:39,815
 AS SHOWN BY MY MOVIE HERE.

2840
02:31:39,815 --> 02:31:45,354
 SO WHAT IS IN THE T CELL

2841
02:31:45,354 --> 02:31:45,821
 RECEPTOR?

2842
02:31:45,821 --> 02:31:47,356
 WHAT DO WE SEE?

2843
02:31:47,356 --> 02:31:49,391
 WE LOOKED TO SEE ARE THEY

2844
02:31:49,391 --> 02:31:52,361
 ACTIVATED OR NOT AND WHAT WE

2845
02:31:52,361 --> 02:31:53,962
 SEE VERY CLEARLY IS THEY ARE

2846
02:31:53,962 --> 02:31:55,597
 ACTIVATED AND WITHIN THE T

2847
02:31:55,597 --> 02:31:57,766
 CELLS YOU NOT ONLY GET THE

2848
02:31:57,766 --> 02:32:06,508
 FOUR LEGGED FORMS AND THE T 

2849
02:32:06,508 --> 02:32:11,580
 CELL RECEPTORS CHANGE, THE

2850
02:32:11,580 --> 02:32:14,450
 ECTOSOMES PICK UP THE

2851
02:32:14,450 --> 02:32:15,918
 ACTIVATED T CELLS.

2852
02:32:15,918 --> 02:32:18,654
 SO QUANTITATING THIS, WE FOUND

2853
02:32:18,654 --> 02:32:20,823
 THE VARIOUS CHANGES TO THE T

2854
02:32:20,823 --> 02:32:31,333
 CELL THERE AND ALSO FOUND

2855
02:32:40,743 --> 02:32:42,111
 TKPWHREUS ROLL THERE.

2856
02:32:42,111 --> 02:32:43,479
 SO WHY?

2857
02:32:43,479 --> 02:32:45,614
 WELL, MY COLLEAGUE WHO SHOWED

2858
02:32:45,614 --> 02:32:47,683
 ME SOME FANTASTIC PAPERS FROM

2859
02:32:47,683 --> 02:32:49,184
 THE 70s WHERE THEY WERE

2860
02:32:49,184 --> 02:32:52,388
 LOOKING AT THIS IN TERMS OF

2861
02:32:52,388 --> 02:32:56,692
 SHEDDING BUT ESSENTIALLY 

2862
02:32:56,692 --> 02:32:59,795
 LOOKING FOR ECTOCYTOSIS IN THE

2863
02:32:59,795 --> 02:33:00,295
 CELLS.

2864
02:33:00,295 --> 02:33:08,137
 CHEMICALLY THEY COULD SHOW IT 

2865
02:33:08,137 --> 02:33:09,505
 WAS ENRICHED WITH TKPWHREUS

2866
02:33:09,505 --> 02:33:14,376
 ROLL WHICH IS A CONE SHAPED

2867
02:33:14,376 --> 02:33:16,011
 DISEASE, HAD ITS HEAD CHOPPED

2868
02:33:16,011 --> 02:33:18,080
 OFF AND IT WOULD CAUSE AN

2869
02:33:18,080 --> 02:33:19,648
 OUTWARD BUDDING OF THE

2870
02:33:19,648 --> 02:33:21,450
 MEMBRANE.

2871
02:33:21,450 --> 02:33:26,155
 SO THIS RAISES THE REALLY GOOD

2872
02:33:26,155 --> 02:33:27,656
 QUESTION THAT THE SHEDDING

2873
02:33:27,656 --> 02:33:32,394
 COULD BE INVOLVED IN

2874
02:33:32,394 --> 02:33:33,295
 ECTOCYTOSIS.

2875
02:33:33,295 --> 02:33:37,032
 THE REAL QUESTION IS HOW DO WE

2876
02:33:37,032 --> 02:33:38,434
 VISUALIZE THAT?

2877
02:33:38,434 --> 02:33:44,306
 SO WE INJECT THE CELLS WITH A

2878
02:33:44,306 --> 02:33:46,108
 PRO TKPWHREUS ROLL, HERE IS

2879
02:33:46,108 --> 02:33:47,876
 THE TARGET CELL AND THIS IS

2880
02:33:47,876 --> 02:33:49,578
 WHAT HAPPENS.

2881
02:33:49,578 --> 02:33:54,483
 IT IS LIKE A LITTLE BIOPROBE

2882
02:33:54,483 --> 02:33:58,554
 PINNING MACHINE WHERE THEY BUD

2883
02:33:58,554 --> 02:34:01,523
 OFF WITH THE T CELL INSIDE

2884
02:34:01,523 --> 02:34:02,424
 THOSE STRUCTURES.

2885
02:34:02,424 --> 02:34:04,660
 SO THIS BRINGS US TO A MODEL

2886
02:34:04,660 --> 02:34:05,828
 WHICH IS THAT UPON

2887
02:34:05,828 --> 02:34:08,063
 RECOGNITION, SO THIS IS THE T

2888
02:34:08,063 --> 02:34:11,767
 CELL ON THE BOTTOM, THE

2889
02:34:11,767 --> 02:34:16,171
 BIOPROBE ON THE TOP, TARGETING

2890
02:34:16,171 --> 02:34:21,109
 BY THE T CELL RECEPTOR AND YOU

2891
02:34:21,109 --> 02:34:22,377
 GET ACTIVATION WITH TKPWHREUS

2892
02:34:22,377 --> 02:34:22,911
 ROLL.

2893
02:34:22,911 --> 02:34:26,348
 AS IT BUILDS UP, IT INITIATES

2894
02:34:26,348 --> 02:34:34,156
 THE OUTWARD BUDDING THAT STAYS

2895
02:34:34,156 --> 02:34:36,091
 IN CONTACT WITH THE BUDDING

2896
02:34:36,091 --> 02:34:42,631
 CELL AND ACTIVATES THE T CELL

2897
02:34:42,631 --> 02:34:43,665
 AND THEN SHEDS.

2898
02:34:43,665 --> 02:34:46,668
 SO IN THIS WAY, WHAT THE MODEL

2899
02:34:46,668 --> 02:34:57,246
 SHOWS IS THE T CELL ACTIVATION

2900
02:35:00,849 --> 02:35:06,822
 SEAMLESSLY ACTIVATES TO 

2901
02:35:06,822 --> 02:35:08,657
 TERMINATION AND RELEASE OF

2902
02:35:08,657 --> 02:35:10,526
 MORE T CELLS.

2903
02:35:10,526 --> 02:35:13,662
 WHAT WE HAVE FOUND IS THIS IS

2904
02:35:13,662 --> 02:35:16,598
 WIDELY USED IN MANY BIOLOGICAL

2905
02:35:16,598 --> 02:35:18,834
 SYSTEMS OTHER THAN THE ONE I

2906
02:35:18,834 --> 02:35:19,501
 JUST SHOWED YOU.

2907
02:35:19,501 --> 02:35:23,839
 THE SAME THING IS HAPPENING IN

2908
02:35:23,839 --> 02:35:34,349
 SILIA, THEY SHED THE ACTIN

2909
02:35:42,658 --> 02:35:44,393
 ACTIVATED RECEPTORS AND SO I

2910
02:35:44,393 --> 02:35:48,030
 WOULD LIKE TO THANK THE MANY

2911
02:35:48,030 --> 02:35:50,966
 CONTRIBUTORS TO MY WORK AND

2912
02:35:50,966 --> 02:35:51,934
 CAN TAKE ANY QUESTIONS.

2913
02:35:51,934 --> 02:35:53,402
 >>  THANK YOU FOR THE

2914
02:35:53,402 --> 02:35:54,803
 WONDERFUL TALK.

2915
02:35:54,803 --> 02:35:59,441
 IS THERE ANY CONTEXT TO THE

2916
02:35:59,441 --> 02:36:00,776
 TARGET CELL, IS THERE A

2917
02:36:00,776 --> 02:36:02,811
 CONSEQUENCE TO THE CELL AND

2918
02:36:02,811 --> 02:36:04,212
 SECONDLY WHEN YOU MENTION IT

2919
02:36:04,212 --> 02:36:08,617
 DOES NOT GO IN THE TARGET CELL

2920
02:36:08,617 --> 02:36:10,886
 IS THAT BECAUSE IT DOESN'T OR

2921
02:36:10,886 --> 02:36:12,487
 DROPS OFF AND --

2922
02:36:12,487 --> 02:36:15,591
 >>  WELL, FIRST OF ALL,
THE

2923
02:36:15,591 --> 02:36:17,659
 CD8 DOES GO IN.

2924
02:36:17,659 --> 02:36:20,729
 WE HAVE NOT LOOKED AT THAT IN

2925
02:36:20,729 --> 02:36:24,466
 DETAIL BUT I KEEP TELLING JANE

2926
02:36:24,466 --> 02:36:27,936
 LET'S LOOK AT CD4'S WHICH ARE

2927
02:36:27,936 --> 02:36:29,638
 VERY INTERESTING BECAUSE THEY

2928
02:36:29,638 --> 02:36:31,239
 ARE NOT BEING KILLED.

2929
02:36:31,239 --> 02:36:32,741
 PERSONALLY I DON'T THINK THEY

2930
02:36:32,741 --> 02:36:33,976
 INFECT, I THINK THIS IS A WAY

2931
02:36:33,976 --> 02:36:40,482
 TO GET RID OF YOUR ACTIVATED

2932
02:36:40,482 --> 02:36:40,849
 RECEPTOR.

2933
02:36:40,849 --> 02:36:44,386
 BUT I READ YOUR PAPERS WHEN I

2934
02:36:44,386 --> 02:36:45,487
 WAS WRITING THIS.

2935
02:36:45,487 --> 02:36:48,757
 >> MY NAME IS NATALIE AND
I AM

2936
02:36:48,757 --> 02:36:51,360
 A PH.D. STUDENT VISITING FROM

2937
02:36:51,360 --> 02:36:51,760
 MOUNT SINAI.

2938
02:36:51,760 --> 02:36:53,128
 I LOVED YOUR TALK.

2939
02:36:53,128 --> 02:36:54,296
 TWO QUESTIONS, JUMPING OFF OF

2940
02:36:54,296 --> 02:36:55,664
 THAT ONE, DO YOU THINK THE

2941
02:36:55,664 --> 02:36:58,867
 IMPORTANCE OF THIS PROCESS IS

2942
02:36:58,867 --> 02:37:03,505
 MORE TO CREATE THE T CELL

2943
02:37:03,505 --> 02:37:04,539
 FURTHER DISCONNECTING FROM

2944
02:37:04,539 --> 02:37:10,712
 THAT SYNAPSE OR THE CARGO THAT

2945
02:37:10,712 --> 02:37:14,383
 IS TRANSFERRING AND PERHAPS

2946
02:37:14,383 --> 02:37:14,783
 BOTH?

2947
02:37:14,783 --> 02:37:18,787
 SO IT IS TOTALLY NOT, IT IS

2948
02:37:18,787 --> 02:37:22,491
 LAGGING BEHIND SO IT TAKES SIX

2949
02:37:22,491 --> 02:37:28,530
 MINUTES TO GET THE LISOSOMES

2950
02:37:28,530 --> 02:37:29,731
 OUT SO I THINK IT IS REQUIRED

2951
02:37:29,731 --> 02:37:33,402
 FOR THE KILLING AND CERTAINLY

2952
02:37:33,402 --> 02:37:35,604
 IN CTL WHICH ARE RECOGNIZING

2953
02:37:35,604 --> 02:37:35,937
 TARGETS.

2954
02:37:35,937 --> 02:37:43,712
 I MEAN THE TARGETS, THEY DO GO

2955
02:37:43,712 --> 02:37:45,013
 TO HELL.

2956
02:37:45,013 --> 02:37:46,782
 >> I HAVE ANOTHER
QUESTION --

2957
02:37:46,782 --> 02:37:50,285
 >> WE CAN TALK AFTER.

2958
02:37:50,285 --> 02:37:51,153
 >> THANKS, JILLIAN, THAT
WAS

2959
02:37:51,153 --> 02:37:51,987
 GORGEOUS.

2960
02:37:51,987 --> 02:37:53,121
 SO I HAVE A QUESTION.

2961
02:37:53,121 --> 02:37:58,527
 WE CAN CONSIDER THIS IS A 

2962
02:37:58,527 --> 02:37:59,594
 MECHANISM THAT ENABLES TO

2963
02:37:59,594 --> 02:38:02,631
 KILL, WHAT IS THE IMPORTANCE

2964
02:38:02,631 --> 02:38:13,208
 OF THE T CELL THAT ENABLES THE

2965
02:38:14,476 --> 02:38:14,710
 SYNAPSE?

2966
02:38:14,710 --> 02:38:15,210
 >> GREAT QUESTION.

2967
02:38:15,210 --> 02:38:16,578
 I DON'T KNOW THE ANSWER.

2968
02:38:16,578 --> 02:38:19,548
 MAYBE IT IS THE T CELLS

2969
02:38:19,548 --> 02:38:19,948
 THEMSELVES.

2970
02:38:19,948 --> 02:38:21,616
 >> GREAT TALK.

2971
02:38:21,616 --> 02:38:32,194
 HAVE YOU IDENTIFY WHETHER THE 

2972
02:38:32,861 --> 02:38:34,730
 PHENOMENON OCCURS DEPENDENTLY

2973
02:38:34,730 --> 02:38:37,833
 OR INDEPENDENT PENDLY OF THE T

2974
02:38:37,833 --> 02:38:38,767
 CELL FORMATION?

2975
02:38:38,767 --> 02:38:39,701
 >> OH, INTERESTING
QUESTION.

2976
02:38:39,701 --> 02:38:41,670
 NO, WE DIDN'T DO IT.

2977
02:38:41,670 --> 02:38:47,209
 >> IS IT WHEN THE T CELL
IS

2978
02:38:47,209 --> 02:38:50,378
 ACTIVATED OR ONLY THE

2979
02:38:50,378 --> 02:38:50,812
 RELEASE --

2980
02:38:50,812 --> 02:38:52,681
 >> IT IS MORE DIFFICULT
TO

2981
02:38:52,681 --> 02:38:54,116
 IMAGE BECAUSE YOU DON'T HAVE

2982
02:38:54,116 --> 02:38:56,384
 THE LEVEL ON THESE THINGS BUT

2983
02:38:56,384 --> 02:39:00,155
 AGAIN, I WILL NEED TO DO THIS.

2984
02:39:00,155 --> 02:39:02,524
 >> HOW DOES THE TARGET
CELL

2985
02:39:02,524 --> 02:39:04,126
 TAKE A CLASS FORM WHICH

2986
02:39:04,126 --> 02:39:10,398
 DOESN'T HAVE THE SIGNAL FOR

2987
02:39:10,398 --> 02:39:10,899
 ENDOCYTOSIS?

2988
02:39:10,899 --> 02:39:12,667
 OR HOW DOES IT GET TAKEN OUT

2989
02:39:12,667 --> 02:39:14,169
 OR DOES IT MATTER?

2990
02:39:14,169 --> 02:39:17,839
 THERE MUST BE CELLS THAT DO IT

2991
02:39:17,839 --> 02:39:18,373
 BETTER THAN OTHERS.

2992
02:39:18,373 --> 02:39:19,674
 >> A NUMBER OF TARGET
CELLS

2993
02:39:19,674 --> 02:39:21,409
 KILL VERY WELL AND THEY ALL

2994
02:39:21,409 --> 02:39:22,711
 SEEM TO TAKE IT UP.

2995
02:39:22,711 --> 02:39:28,350
 ARE YOU SURE THERE IS NOT

2996
02:39:28,350 --> 02:39:28,817
 ANY --

2997
02:39:28,817 --> 02:39:35,457
 >> ANY MOW TEASE, MOST OF
--

2998
02:39:35,457 --> 02:39:37,025
 MOTIFS, MOST OF THEM DON'T.

2999
02:39:37,025 --> 02:39:38,760
 >> YEAH, I WILL HAVE TO
GET

3000
02:39:38,760 --> 02:39:40,829
 BACK TO YOU ON THAT ONE.

3001
02:39:40,829 --> 02:39:42,697
 >> GIVEN THE DIFFERENCES
THAT

3002
02:39:42,697 --> 02:39:45,500
 HAVE BEEN CHARACTERIZED IN THE

3003
02:39:45,500 --> 02:39:46,701
 IMMUNE SYNAPSE BETWEEN

3004
02:39:46,701 --> 02:39:49,771
 STANDARD T CELL AND A CARD T

3005
02:39:49,771 --> 02:39:54,910
 CELL, YOU THINK THIS TEN NONE

3006
02:39:54,910 --> 02:39:57,212
 NONE WILL OCCUR FOR CARD T?

3007
02:39:57,212 --> 02:40:00,448
 >> YEAH, THAT'S WHAT I
REALLY

3008
02:40:00,448 --> 02:40:01,817
 WANT TO DO NEXT.

3009
02:40:01,817 --> 02:40:02,517
 >> GREAT TALK.

3010
02:40:02,517 --> 02:40:06,454
 ARE THE T CELLS ALSO GETTING

3011
02:40:06,454 --> 02:40:06,888
 POPULATED --

3012
02:40:06,888 --> 02:40:08,123
 >> YEAH, WE'RE TRYING TO
LOOK

3013
02:40:08,123 --> 02:40:08,456
 AT THAT.

3014
02:40:08,456 --> 02:40:10,158
 IT IS DIFFICULT TO LOOK AT

3015
02:40:10,158 --> 02:40:15,096
 BECAUSE THESE ARE THINGS THAT

3016
02:40:15,096 --> 02:40:17,399
 PEOPLE LIKE GET EXTRA CELLULAR

3017
02:40:17,399 --> 02:40:18,667
 VEHICLES AND SPIN THEM DOWN

3018
02:40:18,667 --> 02:40:21,469
 AND IT IS VERY, VERY DIRTY.

3019
02:40:21,469 --> 02:40:24,906
 >> SO FOR EXAMPLE THE
C28.

3020
02:40:24,906 --> 02:40:26,174
 >> YEAH, WE HAVEN'T
LISTED

3021
02:40:26,174 --> 02:40:28,243
 THAT YET BUT IT IS ON THE

3022
02:40:28,243 --> 02:40:28,944
 TO-DO LIST.

3023
02:40:28,944 --> 02:40:32,047
 IT IS A LONG TO-DO LIST, JUST

3024
02:40:32,047 --> 02:40:35,517
 AS WELL IF I AM WRITING A

3025
02:40:35,517 --> 02:40:36,351
 GRAPH.

3026
02:40:36,351 --> 02:40:37,152
 >> ENJOYED YOUR TALK.

3027
02:40:37,152 --> 02:40:39,087
 MY QUESTION IS CAN YOU USE

3028
02:40:39,087 --> 02:40:39,988
 THIS MECHANISM TO DELIVER

3029
02:40:39,988 --> 02:40:44,125
 SOMETHING OTHER THAN THE TCR

3030
02:40:44,125 --> 02:40:47,462
 TO YOUR TARGET CELL?

3031
02:40:47,462 --> 02:40:48,730
 >> YEAH, THERE IS A PIECE
IN

3032
02:40:48,730 --> 02:40:52,400
 NATURE THIS WEEK ABOUT USING

3033
02:40:52,400 --> 02:40:55,103
 EXTRA CELLULAR VEHICLES AS A

3034
02:40:55,103 --> 02:40:55,570
 DELIVERY SYSTEM.

3035
02:40:55,570 --> 02:40:57,305
 I DON'T THINK THIS IS -- THEY

3036
02:40:57,305 --> 02:40:58,607
 ARE VERY SMALL, MANY OF THEM.

3037
02:40:58,607 --> 02:41:00,976
 I DON'T KNOW THAT YOU COULD

3038
02:41:00,976 --> 02:41:01,977
 DIRECT SECRETION BECAUSE THEN

3039
02:41:01,977 --> 02:41:04,913
 YOU STILL HAVE A MEMBRANE

3040
02:41:04,913 --> 02:41:06,715
 AROUND IT.

3041
02:41:06,715 --> 02:41:08,116
 SO I'M SITTING ON THE FENCE

3042
02:41:08,116 --> 02:41:09,284
 WITH THAT ONE.

3043
02:41:09,284 --> 02:41:14,723
 I PROBABLY AM ON THE NEGATIVE

3044
02:41:14,723 --> 02:41:15,490
 SIDE.

3045
02:41:15,490 --> 02:41:25,901
 >> HAVE YOU TRIED
MANIPULATING

3046
02:41:25,901 --> 02:41:27,068
 DIAZEGLYCEROL TO SEE WHETHER

3047
02:41:27,068 --> 02:41:29,537
 THAT WOULD BE EFFECTIVE OR

3048
02:41:29,537 --> 02:41:30,038
 NOT?

3049
02:41:30,038 --> 02:41:32,674
 >> YEAH, WE HAVE A GREAT

3050
02:41:32,674 --> 02:41:34,276
 COLLABORATION WITH A CHEMIST

3051
02:41:34,276 --> 02:41:35,577
 AND ARE DOING THIS EXPERIMENT.

3052
02:41:35,577 --> 02:41:37,078
 >> AND WHAT WOULD BE THE

3053
02:41:37,078 --> 02:41:39,814
 ADVANTAGE OF THIS FOR OTHER

3054
02:41:39,814 --> 02:41:40,782
 CELL TYPES?

3055
02:41:40,782 --> 02:41:42,384
 YES, THIS WILL ALOU SERIAL

3056
02:41:42,384 --> 02:41:45,086
 KILLING BUT IF YOU THINK IT IS

3057
02:41:45,086 --> 02:41:47,956
 MORE BROAD A PHENOMENA, I AM

3058
02:41:47,956 --> 02:41:51,226
 JUST CURIOUS IF IT WORKS --

3059
02:41:51,226 --> 02:41:54,162
 >> WE CAN DISCUSS THAT --

3060
02:41:54,162 --> 02:41:58,533
>> FOR EXAMPLE, SYLVIA
WANT%

3061
02:41:58,533 --> 02:42:05,206
 CILIA WANT TO SHED THEIR

3062
02:42:05,206 --> 02:42:07,442
 ACTIVE RESEPARATETO --

3063
02:42:07,442 --> 02:42:08,643
 RECEPTORS AND MAYBE THAT IS

3064
02:42:08,643 --> 02:42:12,647
 WHY WE SEE SO MANY OF THEM.

3065
02:42:12,647 --> 02:42:13,181
 >> LOVELY TALK.

3066
02:42:13,181 --> 02:42:15,250
 YOU ALSO HAVE A PAPER THAT

3067
02:42:15,250 --> 02:42:16,985
 SHOWS YOU CAN'T DISENGAGE

3068
02:42:16,985 --> 02:42:19,454
 TARGETS IF YOU DON'T DELIVER A

3069
02:42:19,454 --> 02:42:22,223
 LETHAL HIT --

3070
02:42:22,223 --> 02:42:23,758
 >> I DISAGREE.

3071
02:42:23,758 --> 02:42:30,332
 >> AND AS IN PERFERO

3072
02:42:30,332 --> 02:42:30,999
 INEFFICIENT T CELLS.

3073
02:42:30,999 --> 02:42:33,535
 HOW DO YOU FIT THAT WITH YOUR

3074
02:42:33,535 --> 02:42:34,069
 DATA?

3075
02:42:34,069 --> 02:42:34,803
 >> THAT IS VERY DIFFERENT

3076
02:42:34,803 --> 02:42:39,674
 WHERE YOU HAVE PERFERO

3077
02:42:39,674 --> 02:42:40,909
 INEFFICIENT GOING ON.

3078
02:42:40,909 --> 02:42:44,913
 BASICALLY THEY DON'T RECOGNIZE

3079
02:42:44,913 --> 02:42:47,682
 SO THEY CONSTANTLY MANUFACTURE

3080
02:42:47,682 --> 02:42:49,818
 MORE T CELL RECEPTORS AND

3081
02:42:49,818 --> 02:42:56,491
 CONSTANTLY ARE ENGAGED AND 

3082
02:42:56,491 --> 02:42:57,125
 ACTIVATED.

3083
02:42:57,125 --> 02:42:59,828
 SO WHILE SOME DO AND OTHERS

3084
02:42:59,828 --> 02:43:01,262
 DON'T AND WHY?

3085
02:43:01,262 --> 02:43:09,270
 WE DON'T QUITE KNOW. 

3086
02:43:09,270 --> 02:43:10,205
 >> THANK YOU.

3087
02:43:10,205 --> 02:43:10,572
 [APPLAUSE]

3088
02:43:10,572 --> 02:43:12,540
 >> ALL RIGHT, IT IS MY

3089
02:43:12,540 --> 02:43:13,808
 PLEASURE TO INTRODUCE

3090
02:43:13,808 --> 02:43:16,811
 CHRISTIAN MEYER WHO IS AN

3091
02:43:16,811 --> 02:43:19,247
 ADMIN INVESTIGATOR HERE AT NCI

3092
02:43:19,247 --> 02:43:23,385
 AND WILL TALK ABOUT T CELLS

3093
02:43:23,385 --> 02:43:24,285
 AND REPERTOIRE SELECTION.

3094
02:43:24,285 --> 02:43:24,986
 >> THANK YOU VERY MUCH.

3095
02:43:24,986 --> 02:43:26,855
 SO FIRST I WOULD LIKE TO THANK

3096
02:43:26,855 --> 02:43:28,323
 THE ORGANIZERS FOR THE

3097
02:43:28,323 --> 02:43:30,158
 INVITATION TO PRESENT AND ALSO

3098
02:43:30,158 --> 02:43:32,694
 FOR PUTTING TOGETHER THIS

3099
02:43:32,694 --> 02:43:33,194
 FANTASTIC CONTENT.

3100
02:43:33,194 --> 02:43:36,131
 SO TODAY I WOULD LIKE TO SHARE

3101
02:43:36,131 --> 02:43:38,566
 UNPUBLISHED DATA FROM MY LAB

3102
02:43:38,566 --> 02:43:43,004
 AND SOMETHING ABOUT WHERE AND

3103
02:43:43,004 --> 02:43:44,806
 WHEN THESE T CELLS CLUSTER AND

3104
02:43:44,806 --> 02:43:46,374
 THE IMPORTANCE IN THE UNITS.

3105
02:43:46,374 --> 02:43:51,780
 SO AS WE ALL KNOW, B CELLS

3106
02:43:51,780 --> 02:43:53,248
 UNDER GO CONCENTRATION IN THE

3107
02:43:53,248 --> 02:43:58,219
 BONE MARROW AND THIS RESULTS

3108
02:43:58,219 --> 02:44:01,122
 HIGHLY IN UNIQUE B CELL ON THE

3109
02:44:01,122 --> 02:44:01,790
 SURFACE.

3110
02:44:01,790 --> 02:44:04,692
 WHEN IT RECEIVES ANTIGEN, IT

3111
02:44:04,692 --> 02:44:05,960
 BECOMES ACTIVATED AND THEN

3112
02:44:05,960 --> 02:44:07,062
 DIFFERENT THINGS CAN HAPPEN.

3113
02:44:07,062 --> 02:44:17,539
 ONE OF THE RESPONSES TO

3114
02:44:17,806 --> 02:44:19,140
 PROTEIN ANTIGEN, BUT ADULTS

3115
02:44:19,140 --> 02:44:20,775
 ALSO HAVE B CELLS IN THE ORGAN

3116
02:44:20,775 --> 02:44:24,112
 AND THEY CAN BE SEGREGATED IN

3117
02:44:24,112 --> 02:44:25,513
 TWO ANATOMIC DEPARTMENTS AND

3118
02:44:25,513 --> 02:44:26,781
 THESE ARE CALLED LIGHT ZONES

3119
02:44:26,781 --> 02:44:28,883
 AND DARK ZONES AND WE KNOW THE

3120
02:44:28,883 --> 02:44:30,185
 PROCESS GOING ON IN EACH OF

3121
02:44:30,185 --> 02:44:31,052
 THE CELLS.

3122
02:44:31,052 --> 02:44:34,823
 THE LIGHT ZONE IS THE AFFINITY

3123
02:44:34,823 --> 02:44:36,858
 BASED SELECTION OF THE B CELL

3124
02:44:36,858 --> 02:44:39,327
 AND THE DARK ZONE ARE THE

3125
02:44:39,327 --> 02:44:40,695
 HELPER CELLS REACTIVE TO THE

3126
02:44:40,695 --> 02:44:42,497
 SAME ANT BEN.

3127
02:44:42,497 --> 02:44:44,265
 IN CONTRAST, IN THE DARK ZONE

3128
02:44:44,265 --> 02:44:47,735
 WHICH IS THE SECOND MECHANISM

3129
02:44:47,735 --> 02:44:51,439
 BY WHICH THEY GENERATE

3130
02:44:51,439 --> 02:44:56,311
 DIVERSITY. 

3131
02:44:56,311 --> 02:45:03,251
 THIS IS DRIVEN BY THE VDJ AND

3132
02:45:03,251 --> 02:45:06,521
 CREATES VARIANTS OF THE B 

3133
02:45:06,521 --> 02:45:12,160
 CELERY SEPTEMBER TORE AND THIS

3134
02:45:12,160 --> 02:45:13,828
 CAUSES SOMATIC HYPER MUTATION.

3135
02:45:13,828 --> 02:45:22,504
 SO IT IS TOUT TO BE THE

3136
02:45:22,504 --> 02:45:23,638
 MECHANISM OF --

3137
02:45:23,638 --> 02:45:24,873
 [INDISCERNIBLE]

3138
02:45:24,873 --> 02:45:27,075
 AND THEN FINALLY THE B ELSE

3139
02:45:27,075 --> 02:45:30,845
 AND PLASMA CELLS CAN BE

3140
02:45:30,845 --> 02:45:33,915
 RELEASED IN THE CENTER AND

3141
02:45:33,915 --> 02:45:42,323
 THIS IS ANOTHER EXAMPLE OF

3142
02:45:42,323 --> 02:45:44,826
 CROSS REGENERATION SO THERE IS

3143
02:45:44,826 --> 02:45:47,695
 THIS QUESTION OF WHETHER THE B

3144
02:45:47,695 --> 02:45:56,771
 CELLS CAN BE GENERATED DURING

3145
02:45:56,771 --> 02:45:57,705
 BCR.

3146
02:45:57,705 --> 02:46:03,611
 SO THERE ARE TWO TYPES OF B

3147
02:46:03,611 --> 02:46:07,182
 CELL AND WHEN WE THINK OF AN

3148
02:46:07,182 --> 02:46:09,951
 AUTO REACTIVE B CELL THAT

3149
02:46:09,951 --> 02:46:12,420
 FEEDS A RECEPTOR, FOR EXAMPLE,

3150
02:46:12,420 --> 02:46:16,791
 ONE OUGHT TO RECOGNIZE ONE

3151
02:46:16,791 --> 02:46:18,726
 ANTIGENUINE AND NOT ANOTHER

3152
02:46:18,726 --> 02:46:22,497
 ANTIGENUINE BUT WE ALSO KNOW

3153
02:46:22,497 --> 02:46:26,501
 THERE ARE POLY REACTIVE B

3154
02:46:26,501 --> 02:46:29,571
 CELLS THAT ARE AUTO REACTIVE

3155
02:46:29,571 --> 02:46:30,972
 FOR ANTIGEN AND NO ANTIGEN AND

3156
02:46:30,972 --> 02:46:34,175
 BOTH OF THESE HAVE TO BE

3157
02:46:34,175 --> 02:46:35,076
 CONTROLLED BECAUSE OTHERWISE

3158
02:46:35,076 --> 02:46:38,713
 IT CAUSES A RISK TO CREATE

3159
02:46:38,713 --> 02:46:39,147
 AUTO IMMUNITY.

3160
02:46:39,147 --> 02:46:48,590
 AND WE KNOW OF THESE

3161
02:46:48,590 --> 02:46:56,864
 MECHANISMS AND THIS IS FROM MY

3162
02:46:56,864 --> 02:46:57,498
 LAB.

3163
02:46:57,498 --> 02:47:00,368
 HOWEVER, B CELL DEVELOPING IN

3164
02:47:00,368 --> 02:47:01,836
 THE BONE MARROW WHICH

3165
02:47:01,836 --> 02:47:04,439
 CONTINUES EDITING FOR THE

3166
02:47:04,439 --> 02:47:07,642
 ARRANGEMENT FOR HEALTHY

3167
02:47:07,642 --> 02:47:08,343
 ACCESS.

3168
02:47:08,343 --> 02:47:15,383
 SOMETHING SIMILAR IS GOING ON 

3169
02:47:15,383 --> 02:47:19,487
 IN THE MECHANISM RECEPTOR.

3170
02:47:19,487 --> 02:47:28,563
 IN A NORMAL REPERTOIRE, IT IS 

3171
02:47:28,563 --> 02:47:30,431
 NOT FULLY UNDERSTOOD IF

3172
02:47:30,431 --> 02:47:31,766
 GERMINATION OCCURS AND IF IT

3173
02:47:31,766 --> 02:47:35,770
 IS TO CREATE HEALTHY IMMUNITY.

3174
02:47:35,770 --> 02:47:37,972
 SO HOW DO WE SOLVE THIS

3175
02:47:37,972 --> 02:47:45,513
 PROBLEM AND IDENTIFY THE

3176
02:47:45,513 --> 02:47:46,147
 MECHANISM?

3177
02:47:46,147 --> 02:47:52,186
 WE DOES THE CLONAL DELETION 

3178
02:47:52,186 --> 02:47:54,088
 OCCUR PHYSICAL LOGICALLY?

3179
02:47:54,088 --> 02:48:01,829
 SO WE LOOK AT THE ROSA 26 

3180
02:48:01,829 --> 02:48:09,237
 APOPTOSIS IN INDICATOR MICE

3181
02:48:09,237 --> 02:48:12,440
 WITH FRET AND WITH APOPTOSIS,

3182
02:48:12,440 --> 02:48:17,078
 YOU CAN SEE THE LOSS OF FRET.

3183
02:48:17,078 --> 02:48:19,580
 FROM THE DONOR TO THE

3184
02:48:19,580 --> 02:48:23,484
 RECEPTOR, YOU CAN SEE THE FRET

3185
02:48:23,484 --> 02:48:27,555
 LOSS IN TWO DISTINCT 

3186
02:48:27,555 --> 02:48:28,456
 POPULATIONS, ONE CORRESPONDING

3187
02:48:28,456 --> 02:48:30,224
 WHERE THEY HAVE LOST THE

3188
02:48:30,224 --> 02:48:38,633
 SIGNAL AND THE OTHER ONE 

3189
02:48:38,633 --> 02:48:42,103
 RESPONDING TO THE FRET

3190
02:48:42,103 --> 02:48:44,372
 NEGATIVELY.

3191
02:48:44,372 --> 02:48:48,009
 SO WE TO WANT HIGHLIGHT THE

3192
02:48:48,009 --> 02:48:57,018
 FRET BECAUSE IT CAN ACTIVATE

3193
02:48:57,018 --> 02:49:01,522
 MUCH EASIER THEN ILC3 AND IS

3194
02:49:01,522 --> 02:49:02,223
 IMPORTANT IN IMAGING BUT WHAT

3195
02:49:02,223 --> 02:49:06,627
 I WANT TO SHOW YOU TODAY IS

3196
02:49:06,627 --> 02:49:17,171
 THAT THE DETECTION OF ACASP3

3197
02:49:21,309 --> 02:49:23,344
 IS ALMOST IMPOSSIBLE TO SEE.

3198
02:49:23,344 --> 02:49:26,013
 THERE IS HIGH SENSE SIFT AND

3199
02:49:26,013 --> 02:49:27,382
 WE WOULD EXPECT THAT THEY

3200
02:49:27,382 --> 02:49:29,384
 WOULD BE HIGHLY ENRICHED IN

3201
02:49:29,384 --> 02:49:30,351
 THE LIVE CELL.

3202
02:49:30,351 --> 02:49:34,622
 SO FIRST WE QUANTITATED THIS

3203
02:49:34,622 --> 02:49:35,189
 ACROSS PHYSICAL LOGIC

3204
02:49:35,189 --> 02:49:36,491
 DEVELOPMENT AND I WILL SHOW

3205
02:49:36,491 --> 02:49:38,693
 YOU THE DATA AND DEVELOPMENTAL

3206
02:49:38,693 --> 02:49:40,762
 SCHEME AND THEN SHOW THE

3207
02:49:40,762 --> 02:49:44,899
 RESULT DIRECTLY BELOW THE

3208
02:49:44,899 --> 02:49:45,800
 RESPECTIVE DEVELOPMENTAL

3209
02:49:45,800 --> 02:49:46,100
 STAGE.

3210
02:49:46,100 --> 02:49:48,736
 IS IN THE BONE MARROW, THE

3211
02:49:48,736 --> 02:49:54,175
 EARLIEST B CELL EXPRESSES ON

3212
02:49:54,175 --> 02:49:56,477
 THE SURFACE IS THE FRET B CELL

3213
02:49:56,477 --> 02:49:58,446
 AND WE WERE VERY SURPRISED

3214
02:49:58,446 --> 02:50:01,983
 THAT A VERY SMALL FRACTION OF

3215
02:50:01,983 --> 02:50:06,220
 B CELLS THAT WERE IMAGED IS

3216
02:50:06,220 --> 02:50:13,294
 ONLY SLIDE -- SLIGHTLY INSIDE

3217
02:50:13,294 --> 02:50:14,262
 THE BONE MARROW.

3218
02:50:14,262 --> 02:50:16,497
 AS IT FINDS ITS WAY OUT OF THE

3219
02:50:16,497 --> 02:50:20,368
 BONE MARROW, THERE IS ALSO A 

3220
02:50:20,368 --> 02:50:24,472
 VERY LOW FRACTION OF MATURE

3221
02:50:24,472 --> 02:50:24,872
 CELLS.

3222
02:50:24,872 --> 02:50:28,075
 AS THEY ARE RELEASED IN THE

3223
02:50:28,075 --> 02:50:37,185
 BLOOD CIRCULATION, WE CALL

3224
02:50:37,185 --> 02:50:44,292
 THESE TYPE 1B CELLS, WE FIND

3225
02:50:44,292 --> 02:50:46,260
 THERE ARE A QUITE NEGATIVE

3226
02:50:46,260 --> 02:50:49,464
 NUMBER OF B CELLS AND AS

3227
02:50:49,464 --> 02:50:52,033
 DEVELOPMENT CONTINUES, YOU CAN

3228
02:50:52,033 --> 02:50:55,236
 SEE THE LETTER LEVEL OF

3229
02:50:55,236 --> 02:51:05,713
 TRANSITIONAL CELLS AND 

3230
02:51:13,221 --> 02:51:15,723
 DISTINGUISHED BY FOLLICULAL

3231
02:51:15,723 --> 02:51:16,891
 PROCESS.

3232
02:51:16,891 --> 02:51:24,298
 SO WE PERFORMED THIS

3233
02:51:24,298 --> 02:51:27,335
 EXPERIMENT AND THERE WERE HIGH

3234
02:51:27,335 --> 02:51:33,875
 LEVELS OF APOPOSIS IN

3235
02:51:33,875 --> 02:51:35,476
 TRANSITIONAL1 B CELLS.

3236
02:51:35,476 --> 02:51:39,113
 FOR SELFLY YACHTIVITY AND

3237
02:51:39,113 --> 02:51:41,849
 APOPTOSIS DURING B CELL

3238
02:51:41,849 --> 02:51:46,821
 DEVELOPMENT, WE TOOK THE ROSA

3239
02:51:46,821 --> 02:51:48,890
 26-INDIA MOUSE AND SUBJECTED

3240
02:51:48,890 --> 02:51:53,528
 IT TO SINGLE CELL SORTING WITH

3241
02:51:53,528 --> 02:51:56,030
 IMMATURE AND EARLY IMMATURE

3242
02:51:56,030 --> 02:52:05,139
 CELLS AND THIS ALLOWED THEM TO

3243
02:52:05,139 --> 02:52:07,008
 REDUCE IN POLY CELLS.

3244
02:52:07,008 --> 02:52:08,409
 SO WE DON'T HAVE THE TIME TO

3245
02:52:08,409 --> 02:52:11,612
 GO THROUGH ALL OF THIS BUT WE

3246
02:52:11,612 --> 02:52:17,618
 SHOW THE AUTO AND POLY

3247
02:52:17,618 --> 02:52:19,554
 REACTIVITY AND RECOGNIZE THE

3248
02:52:19,554 --> 02:52:21,956
 ACTIVE PART OF THE B CELLS AND

3249
02:52:21,956 --> 02:52:24,325
 FOR THE WIDE TIME THAT THEY

3250
02:52:24,325 --> 02:52:27,395
 WERE GOING OFF, WE RECOGNIZE

3251
02:52:27,395 --> 02:52:29,564
 THE B CELL DEVELOPMENT.

3252
02:52:29,564 --> 02:52:31,966
 SO WE FOUND THAT ABOUT

3253
02:52:31,966 --> 02:52:37,772
 30 PERCENT OF THE B CELLS WERE

3254
02:52:37,772 --> 02:52:38,606
 SELF-REACTIVE.

3255
02:52:38,606 --> 02:52:40,975
 AND THEN WE FOUND THAT THEY

3256
02:52:40,975 --> 02:52:43,411
 SIGNIFICANTLY REDUCE WITHIN

3257
02:52:43,411 --> 02:52:45,446
 THE BONE MARROW AND THERE ARE

3258
02:52:45,446 --> 02:52:49,016
 OTHER FACTORS WITHIN THE FRET

3259
02:52:49,016 --> 02:52:50,651
 COMPARTMENT SO WE WOULD EXPECT

3260
02:52:50,651 --> 02:52:56,991
 IT TO BE HIGHLY ENRICHED WITH

3261
02:52:56,991 --> 02:52:58,059
 POLY CELLS, HOWEVER THIS IS

3262
02:52:58,059 --> 02:53:00,261
 NOT THE CASE AT ALL AND YOU

3263
02:53:00,261 --> 02:53:07,635
 CAN SEE THERE IS NO POLY

3264
02:53:07,635 --> 02:53:08,135
 REACTION ACTIVITY.

3265
02:53:08,135 --> 02:53:10,838
 SO THERE WASN'T A REDUCTION IN

3266
02:53:10,838 --> 02:53:12,873
 B CELL DEVELOPMENT WITHIN THE

3267
02:53:12,873 --> 02:53:15,509
 BONE MARROW BUT THIS WAS NOT

3268
02:53:15,509 --> 02:53:24,318
 YET ASSOCIATED WITH INCREASED

3269
02:53:24,318 --> 02:53:28,155
 IMAGING OF AUTO AND POLY

3270
02:53:28,155 --> 02:53:28,656
 CELLS.

3271
02:53:28,656 --> 02:53:38,666
 SO YOU CAN SEE THE IMAGING WAS

3272
02:53:38,666 --> 02:53:42,903
 ALMOST STABLE BUT IT WAS

3273
02:53:42,903 --> 02:53:45,806
 DIFFICULT TO IMAGE IN THE

3274
02:53:45,806 --> 02:53:46,607
 OTHER DEPARTMENT BECAUSE THIS

3275
02:53:46,607 --> 02:53:49,977
 IS THE B CELL AT ITS PEAK AND

3276
02:53:49,977 --> 02:53:58,285
 IT IS POSSIBLE THEY MIGHT GO

3277
02:53:58,285 --> 02:54:00,488
 THROUGH APOPTIC OR

3278
02:54:00,488 --> 02:54:02,790
 TRANSITIONAL PHASE AND YOU CAN

3279
02:54:02,790 --> 02:54:06,761
 SEE 90 PERCENT OF THE B CELLS

3280
02:54:06,761 --> 02:54:08,663
 ARE DYING FOR DIFFERENT

3281
02:54:08,663 --> 02:54:09,030
 REASONS.

3282
02:54:09,030 --> 02:54:11,265
 SO TO SUMMARIZE WHAT I HAVE

3283
02:54:11,265 --> 02:54:14,835
 SHOWN YOU IN THIS GRAPH, THE

3284
02:54:14,835 --> 02:54:25,413
 RED SHADED AREA WAS THE B CELL

3285
02:54:27,148 --> 02:54:33,821
 SELF REACTIVITY. 

3286
02:54:33,821 --> 02:54:38,926
 THE GREEN IS POLY RECEPTOR

3287
02:54:38,926 --> 02:54:40,795
 CELLS AND BASED ON THESE

3288
02:54:40,795 --> 02:54:42,530
 FINDINGS, WE THINK THIS

3289
02:54:42,530 --> 02:54:46,367
 REDUCTION IN THE BONE MARROW

3290
02:54:46,367 --> 02:54:50,504
 IS NOT DUE TO DELETION BUT

3291
02:54:50,504 --> 02:54:52,039
 OTHER MECHANISMS SUCH AS

3292
02:54:52,039 --> 02:54:52,440
 EDITING.

3293
02:54:52,440 --> 02:55:00,548
 HERE IN THE PERIPHERY IS THIS

3294
02:55:00,548 --> 02:55:04,118
 MAPPED SECTION OF B CELL BUT

3295
02:55:04,118 --> 02:55:06,854
 EDITING REMOVES MOST OF THE

3296
02:55:06,854 --> 02:55:08,322
 SELF-REWRACKIVE B CELLS IN THE

3297
02:55:08,322 --> 02:55:08,656
 MARROW.

3298
02:55:08,656 --> 02:55:10,691
 SO BECAUSE OF THAT, WE THINK

3299
02:55:10,691 --> 02:55:14,161
 THEY ARE NOT SIGNALED TO

3300
02:55:14,161 --> 02:55:14,495
 SURVIVE.

3301
02:55:14,495 --> 02:55:17,998
 SO NOW THIS BRINGS UP THE

3302
02:55:17,998 --> 02:55:20,167
 QUESTION, IF B CELLS ARE AT

3303
02:55:20,167 --> 02:55:22,670
 ALL IMPORTANT FOR CREATING

3304
02:55:22,670 --> 02:55:24,205
 AUTO IMMUNITY?

3305
02:55:24,205 --> 02:55:27,174
 AND THE QUESTION IS YES.

3306
02:55:27,174 --> 02:55:32,146
 WE KNOW EVEN IN MOUSE MODELS

3307
02:55:32,146 --> 02:55:36,650
 THAT B CELLS HAVE DIFFICULTY

3308
02:55:36,650 --> 02:55:45,793
 AND SO WE ASK ROLE OF B CELL

3309
02:55:45,793 --> 02:55:48,696
 APOPTOSIS IN AUTO IMMUNITY.

3310
02:55:48,696 --> 02:55:51,632
 THE ORIGINS OF THIS DISEASE IN

3311
02:55:51,632 --> 02:55:55,035
 THE MOUSE MODEL IS NOT ENGAGED

3312
02:55:55,035 --> 02:55:59,306
 WELL SO WE USE SPONTANEOUS

3313
02:55:59,306 --> 02:56:07,148
 AUTO ANTIBODY PRODUCTION THAT 

3314
02:56:07,148 --> 02:56:11,485
 ALLOWS US TO BE EXPRESSED IN

3315
02:56:11,485 --> 02:56:12,520
 DIFFERENT COMPARTMENTS AND I

3316
02:56:12,520 --> 02:56:14,922
 AM SUMMARIZING THE RESULTS

3317
02:56:14,922 --> 02:56:15,389
 HERE.

3318
02:56:15,389 --> 02:56:19,426
 FIRST WE SCREEN AFTER THESE

3319
02:56:19,426 --> 02:56:22,062
 MICE AGE WITH THE CONTROL

3320
02:56:22,062 --> 02:56:25,232
 MICE, WE HAVE HIGH BODIES AND

3321
02:56:25,232 --> 02:56:27,902
 FOUND ALL THREE GROUPS

3322
02:56:27,902 --> 02:56:31,672
 DEVELOPED HIGH TITERS OF AUTO

3323
02:56:31,672 --> 02:56:32,773
 ANTIBODIES AND COULDN'T

3324
02:56:32,773 --> 02:56:34,108
 MEASURE ANY DIFFERENCE IN THE

3325
02:56:34,108 --> 02:56:36,377
 THREE GROUPS SO THIS SUGGESTS

3326
02:56:36,377 --> 02:56:44,385
 THAT THE AUTO IMMUNITY IS

3327
02:56:44,385 --> 02:56:45,386
 ACTIVATED AFTER DEACTIVATION.

3328
02:56:45,386 --> 02:56:48,589
 BUT IN THE EARLY FINDINGS,

3329
02:56:48,589 --> 02:56:55,196
 WHERE WE LOOK AT APOPTOSIS, 

3330
02:56:55,196 --> 02:57:02,203
 YOU CAN SEE THE MICE WHERE IT 

3331
02:57:02,203 --> 02:57:06,307
 WAS ONLY AFTER IT WAS FOUND IN

3332
02:57:06,307 --> 02:57:06,774
 DISEASE.

3333
02:57:06,774 --> 02:57:09,243
 AND MOREOVER, THE DISEASE

3334
02:57:09,243 --> 02:57:14,114
 FACTOR IN THE MB1 MICE, THESE

3335
02:57:14,114 --> 02:57:16,684
 MICE STARTED DYING ONCE THEY

3336
02:57:16,684 --> 02:57:19,220
 REACHED A CERTAIN AGE.

3337
02:57:19,220 --> 02:57:23,891
 SO I AM SHOWING YOU THE

3338
02:57:23,891 --> 02:57:32,132
 PATHOLOGY AND YOU CAN SEE HERE

3339
02:57:32,132 --> 02:57:34,101
 THE MB3 MICE HAD VERY

3340
02:57:34,101 --> 02:57:37,471
 DIFFERENT CONTROLS THAN THE

3341
02:57:37,471 --> 02:57:40,641
 MB1 MICE SO FROM THIS IT WOULD

3342
02:57:40,641 --> 02:57:44,445
 SUGGEST THE RESULT IS IT

3343
02:57:44,445 --> 02:57:47,081
 INHIBITS DISEASE BUT HAS A

3344
02:57:47,081 --> 02:57:49,817
 VERY SURPRISING MECHANISM.

3345
02:57:49,817 --> 02:57:58,325
 SO TO SUMMARIZE THIS, WE --

3346
02:57:58,325 --> 02:57:58,926
 [INDISCERNIBLE]

3347
02:57:58,926 --> 02:58:00,628
 WHERE APOPTOSIS IS DEVELOPED

3348
02:58:00,628 --> 02:58:04,465
 AND THESE ARE USEFUL TOOLS TO

3349
02:58:04,465 --> 02:58:08,535
 FURTHER DETECT THE EVOLUTION

3350
02:58:08,535 --> 02:58:10,471
 OF THE DISEASE AND ASSOCIATED

3351
02:58:10,471 --> 02:58:10,838
 THERAPY.

3352
02:58:10,838 --> 02:58:12,139
 SO TO SUMMARIZE WHAT I HAVE

3353
02:58:12,139 --> 02:58:18,112
 SHOWN YOU TODAY, WHAT IS THE

3354
02:58:18,112 --> 02:58:23,951
 ROLE IN THE NEPHRITIS

3355
02:58:23,951 --> 02:58:25,653
 DEVELOPMENT, THE B CELLS

3356
02:58:25,653 --> 02:58:28,589
 PROTECT FROM THE DISEASE BUT

3357
02:58:28,589 --> 02:58:35,596
 WE THINK THIS IS NOT BECAUSE

3358
02:58:35,596 --> 02:58:37,898
 OF RECOMBINATION OCCURS BUT BY

3359
02:58:37,898 --> 02:58:39,333
 DIFFERENT MECHANISM, WHEREAS

3360
02:58:39,333 --> 02:58:44,238
 WE THINK HOST ACTIVATION AND

3361
02:58:44,238 --> 02:58:46,407
 MEMORY B CELLS IN PLASMA

3362
02:58:46,407 --> 02:58:48,575
 CELLS, I DIDN'T HAVE THE DATA

3363
02:58:48,575 --> 02:58:51,111
 TO SHOW YOU THIS TIME BUT WE

3364
02:58:51,111 --> 02:58:56,483
 THINK THIS IS THE PLACE WHERE

3365
02:58:56,483 --> 02:59:00,020
 WE GET THE MEMORY B CELL

3366
02:59:00,020 --> 02:59:07,962
 PRODUCTION AND BOTH ACT

3367
02:59:07,962 --> 02:59:10,497
 TOGETHER. 

3368
02:59:10,497 --> 02:59:14,034
 AND THESE ARE VERY CENTRALIZED

3369
02:59:14,034 --> 02:59:19,273
 FOR THE AUTO ANTIBODY

3370
02:59:19,273 --> 02:59:19,773
 PRODUCTION.

3371
02:59:19,773 --> 02:59:23,510
 SO A SUMMARY OF MY WORK,

3372
02:59:23,510 --> 02:59:27,781
 EVERYONE HAS DON'T BOOTED TO

3373
02:59:27,781 --> 02:59:28,749
 THIS WORK, COLLABORATORS AND

3374
02:59:28,749 --> 02:59:39,326
 THANK YOU FOR YOUR ATTENTION.

3375
02:59:42,396 --> 02:59:43,197
 [APPLAUSE]

3376
02:59:43,197 --> 02:59:43,831
 >> HI, GREAT TALK.

3377
02:59:43,831 --> 02:59:46,867
 HOW OLD ARE THE MICE WHEN YOU

3378
02:59:46,867 --> 02:59:52,106
 TRIED FOR THE NEPHRITIS.

3379
02:59:52,106 --> 02:59:54,508
 >> 40 WEEKS OLD.

3380
02:59:54,508 --> 02:59:55,209
 >> 14?

3381
02:59:55,209 --> 02:59:55,542
 >> 40.

3382
02:59:55,542 --> 02:59:57,011
 >> SO MY SECOND QUESTION,
IF

3383
02:59:57,011 --> 03:00:01,815
 YOU WAIT LONGER FOR THE AID,

3384
03:00:01,815 --> 03:00:06,053
 YOU WOULD ALSO DEVELOP

3385
03:00:06,053 --> 03:00:07,321
 NEPHRITIS IN 40 WEEKS?

3386
03:00:07,321 --> 03:00:08,589
 >> GOOD QUESTION.

3387
03:00:08,589 --> 03:00:10,691
 WE HAVEN'T SPACED THEM LONGER

3388
03:00:10,691 --> 03:00:12,159
 BECAUSE 40 WEEKS TAKES A VERY

3389
03:00:12,159 --> 03:00:14,328
 LONG TIME TO GET THE DATA BUT

3390
03:00:14,328 --> 03:00:15,496
 IT IS INTERESTING POINT.

3391
03:00:15,496 --> 03:00:17,097
 IT WOULD BE INTERESTING TO SEE

3392
03:00:17,097 --> 03:00:19,066
 IF THEY CATCH UP EVENTUALLY

3393
03:00:19,066 --> 03:00:29,643
 BUT WE HAVEN'T DONE IT SO FAR.

3394
03:00:32,513 --> 03:00:35,249
 >> OKAY, GREAT TALK,
CHRIS.

3395
03:00:35,249 --> 03:00:40,821
 I WAS WONDERING, WE DID THE

3396
03:00:40,821 --> 03:00:42,489
 CORNELL EXPERIMENT ON

3397
03:00:42,489 --> 03:00:44,892
 CONDITIONS AND WONDERING HOW

3398
03:00:44,892 --> 03:00:47,061
 THIS IS AFFECTED BY INFECTION

3399
03:00:47,061 --> 03:00:52,533
 WHERE YOU HAVE MASS

3400
03:00:52,533 --> 03:00:53,634
 INEFFECTION, WOULD IT BE

3401
03:00:53,634 --> 03:00:59,273
 SIMILAR TO THE ROLE OF

3402
03:00:59,273 --> 03:01:00,274
 APOPTOSIS?

3403
03:01:00,274 --> 03:01:02,042
 >> YOU MEAN IN
DEVELOPMENT OR

3404
03:01:02,042 --> 03:01:02,476
 THE --

3405
03:01:02,476 --> 03:01:04,078
 >> RIGHT, WHEN YOU
CLEANED OUT

3406
03:01:04,078 --> 03:01:06,680
 THE B CELLS TO SEE IF THEY ARE

3407
03:01:06,680 --> 03:01:08,682
 AUTO REACTIVE, THAT WAS ON THE

3408
03:01:08,682 --> 03:01:09,616
 BASELINE CONDITION?

3409
03:01:09,616 --> 03:01:12,052
 >> YES, ON THE BASELINE

3410
03:01:12,052 --> 03:01:13,554
 CONDITIONS, YES.

3411
03:01:13,554 --> 03:01:18,559
 >> SO IF YOU TAKE THE
MOUSE 

3412
03:01:18,559 --> 03:01:20,828
 WHICH HAS MASSIVE EXPANSION

3413
03:01:20,828 --> 03:01:22,663
 DUE TO INFECTION, WHAT WOULD

3414
03:01:22,663 --> 03:01:23,497
 IT SHOW?

3415
03:01:23,497 --> 03:01:27,601
 >> WELL, WE HAVEN'T
LOOKED AT

3416
03:01:27,601 --> 03:01:31,505
 THE MOUSE WITH LYNN EFFECT --

3417
03:01:31,505 --> 03:01:35,609
 INFECTION BUT HAVE LOOKED AT

3418
03:01:35,609 --> 03:01:37,244
 IT AFTER VACCINATION AND --

3419
03:01:37,244 --> 03:01:37,845
 [INDISCERNIBLE]

3420
03:01:37,845 --> 03:01:43,550
 SO IT IS NOT A VERY FREQUENT

3421
03:01:43,550 --> 03:01:46,386
 EVENT EITHER IN VACCINATION OR

3422
03:01:46,386 --> 03:01:46,753
 INFECTION.

3423
03:01:46,753 --> 03:01:48,622
 >>  BECAUSE I WAS
WONDERING

3424
03:01:48,622 --> 03:01:53,660
 SINCE YOU HAVE THE AUTO BODY

3425
03:01:53,660 --> 03:01:54,895
 REACTI THINK VE.

3426
03:01:54,895 --> 03:01:57,364
 >> MY QUESTION IS SIMILAR
TO

3427
03:01:57,364 --> 03:02:00,400
 WHAT HE IS ASKING, GERMA

3428
03:02:00,400 --> 03:02:02,636
 CENTERS, HAVE YOU EVER TRIED

3429
03:02:02,636 --> 03:02:09,042
 TO COMPARE THE GERMA CENTERS

3430
03:02:09,042 --> 03:02:10,777
 WITH APOPTOSIS CENTERS AND

3431
03:02:10,777 --> 03:02:14,014
 WOULD THEY SHOW A SIMILAR

3432
03:02:14,014 --> 03:02:15,215
 SIGNATURE.

3433
03:02:15,215 --> 03:02:21,121
 AND WHERE DO YOU PUT THE T 

3434
03:02:21,121 --> 03:02:23,757
 CELL IN THIS MODEL --

3435
03:02:23,757 --> 03:02:24,224
 [INDISCERNIBLE]

3436
03:02:24,224 --> 03:02:25,959
 >> GOOD QUESTION.

3437
03:02:25,959 --> 03:02:33,800
 WE DIDN'T LOOK AT T CELL, ONLY

3438
03:02:33,800 --> 03:02:35,435
 AT THE --

3439
03:02:35,435 --> 03:02:35,903
 [INDISCERNIBLE]

3440
03:02:35,903 --> 03:02:39,206
 AND TR, THAT IS ALSO A GREAT

3441
03:02:39,206 --> 03:02:41,074
 QUESTION, YEAH, BUT THEY

3442
03:02:41,074 --> 03:02:42,476
 DEFINITELY REGULATE SOMETHING

3443
03:02:42,476 --> 03:02:45,112
 BUT NO.

3444
03:02:45,112 --> 03:02:46,980
 MAYBE NOT SELF REACTIVE BUT I

3445
03:02:46,980 --> 03:02:47,881
 AM NOT SURE.

3446
03:02:47,881 --> 03:02:49,750
 THERE IS A LOT OF WORK YET TO

3447
03:02:49,750 --> 03:02:50,484
 BE DONE.

3448
03:02:50,484 --> 03:02:52,886
 >> THANK YOU SO MUCH.

3449
03:02:52,886 --> 03:02:56,423
 >> SO FOR THE FIRST PART
OF

3450
03:02:56,423 --> 03:02:59,593
 THE TALK, THE ASSUMPTION IS IF

3451
03:02:59,593 --> 03:03:02,362
 YOU SEE ACTIVATION OF CAT 3,

3452
03:03:02,362 --> 03:03:05,666
 THE CELLS ARE IN APOPTOSIS AND

3453
03:03:05,666 --> 03:03:10,270
 I ASK ARE YOU SURE?

3454
03:03:10,270 --> 03:03:17,711
 AND I ASK THE QUESTION BECAUSE

3455
03:03:17,711 --> 03:03:26,386
 THE LITERATURE SHOWS THAT WITH

3456
03:03:26,386 --> 03:03:28,822
 T CELL APOPTOSIS, THEY CLEARLY

3457
03:03:28,822 --> 03:03:32,025
 SURVIVE SO HAVE YOU CLONED THE

3458
03:03:32,025 --> 03:03:34,761
 B CELLS OR LOOKED AT THE CELLS

3459
03:03:34,761 --> 03:03:37,831
 AND IDENTIFIED THEY ARE IN

3460
03:03:37,831 --> 03:03:38,198
 APOPTOSIS?

3461
03:03:38,198 --> 03:03:39,800
 >> THEY DEFINITELY ARE
AND I

3462
03:03:39,800 --> 03:03:41,735
 DIDN'T HAVE TIME TO SHOW ALL

3463
03:03:41,735 --> 03:03:43,604
 THE DATA BUT FOR EXAMPLE, WE

3464
03:03:43,604 --> 03:03:46,573
 DID THE SIDE STAINING THAT

3465
03:03:46,573 --> 03:03:46,940
 OVERLAPS.

3466
03:03:46,940 --> 03:03:49,810
 AND ACTUALLY I WOULD SAY PART

3467
03:03:49,810 --> 03:03:53,680
 OF THE MAIT SPACE, COME FROM

3468
03:03:53,680 --> 03:04:01,622
 MAIT AND THE EARLIEST PROCESS

3469
03:04:01,622 --> 03:04:09,630
 AND WE ALSO COULD DO IT IN VET

3470
03:04:09,630 --> 03:04:12,866
 VITRO AND IN VIVO AND EVERY

3471
03:04:12,866 --> 03:04:18,372
 CELL WOULD APPARENTLY DIE. 

3472
03:04:18,372 --> 03:04:20,073
 >> THANK YOU.

3473
03:04:20,073 --> 03:04:30,350
 [APPLAUSE] 

3474
03:04:40,427 --> 03:04:40,627
 [.

3475
03:04:40,627 --> 03:04:46,266
 [ WITH OFF MIC ]

3476
03:04:46,266 --> 03:04:49,536
 >> THANK YOU AND THANKS
TO THE

3477
03:04:49,536 --> 03:04:52,039
 ORGANIZERS AND FOR THE

3478
03:04:52,039 --> 03:04:52,439
 INVITATION.

3479
03:04:52,439 --> 03:04:55,709
 JUST TRYING TO GET MY BEARINGS

3480
03:04:55,709 --> 03:04:56,576
 HERE.

3481
03:04:56,576 --> 03:04:56,877
 OKAY.

3482
03:04:56,877 --> 03:04:58,945
 SO TODAY I AM GOING TO BE

3483
03:04:58,945 --> 03:05:00,013
 TALKING ABOUT SOME WORK THAT

3484
03:05:00,013 --> 03:05:01,782
 WE HAVE BEEN DOING THAT REALLY

3485
03:05:01,782 --> 03:05:06,286
 CAME OUT OF OUR EARLIER STUDY

3486
03:05:06,286 --> 03:05:07,954
 THAT DEMONSTRATED THAT LDK

3487
03:05:07,954 --> 03:05:09,423
 OCCURS WITH ASSOCIATION AS

3488
03:05:09,423 --> 03:05:19,966
 WELL AS T CELL SILLALLING IN

3489
03:05:21,435 --> 03:05:31,812
 CONVENTIONAL DOCKING AND

3490
03:05:34,514 --> 03:05:35,248
 NONCONVENTIONAL DOCKING.

3491
03:05:35,248 --> 03:05:38,251
 SO THERE ARE TWO PHASES OF THE

3492
03:05:38,251 --> 03:05:42,889
 T CELL LIFE WHERE IT MUST BE

3493
03:05:42,889 --> 03:05:44,124
 LIGATED OR RECOGNIZED TO

3494
03:05:44,124 --> 03:05:46,193
 RECEIVE A SURVIVOR SIGNAL AND

3495
03:05:46,193 --> 03:05:48,495
 ALSO NOT TOO STRONG AN

3496
03:05:48,495 --> 03:05:50,130
 AFFINITY IN ORDER TO SURVIVE

3497
03:05:50,130 --> 03:05:51,031
 NEGATIVE SELECTION AND OF

3498
03:05:51,031 --> 03:05:53,967
 COURSE IN THE PERIPHERY, THE

3499
03:05:53,967 --> 03:05:56,503
 ENGAGEMENT OF THE TCR IS

3500
03:05:56,503 --> 03:05:57,838
 CRITICAL FOR T CELL

3501
03:05:57,838 --> 03:05:58,271
 ACTIVATION.

3502
03:05:58,271 --> 03:06:01,241
 SO WHAT IS REALLY INVOLVED IN

3503
03:06:01,241 --> 03:06:04,678
 THIS INTERACTION, OKAY, SO WE

3504
03:06:04,678 --> 03:06:09,950
 KNOW THAT HERE WE HAVE PMHC IN

3505
03:06:09,950 --> 03:06:13,453
 THE T CELL THAT RECOGNIZES

3506
03:06:13,453 --> 03:06:16,923
 VIRAL PEPTIDE FRAGMENTS IN THE

3507
03:06:16,923 --> 03:06:17,657
 CONTEXT OF MHC.

3508
03:06:17,657 --> 03:06:21,962
 THIS IS A PRIMARY RECOGNITION

3509
03:06:21,962 --> 03:06:32,305
 INTERACTION AND THEN THE THIS

3510
03:06:32,305 --> 03:06:33,940
 THEN INITIATES THE WHOLE

3511
03:06:33,940 --> 03:06:36,843
 SIGNAL AS WE KNOW IT AND THAT

3512
03:06:36,843 --> 03:06:38,145
 HAS BEEN RESULTING,

3513
03:06:38,145 --> 03:06:40,580
 PROLIFERATION OF THE T CELL

3514
03:06:40,580 --> 03:06:44,851
 AND ACTIVATION OF THE EFFECT

3515
03:06:44,851 --> 03:06:46,119
 TORE FUNCTION SO REALLY GOING

3516
03:06:46,119 --> 03:06:48,855
 BACK TO WHAT I AM FOCUSING ON

3517
03:06:48,855 --> 03:06:55,095
 IN THE TALK TODAY IS THIS

3518
03:06:55,095 --> 03:07:02,702
 INTERACTION BETWEEN T CELL AND

3519
03:07:02,702 --> 03:07:03,003
 NTK.

3520
03:07:03,003 --> 03:07:06,306
 SO TODAY THERE HAS BEEN TWO

3521
03:07:06,306 --> 03:07:07,340
 CHARACTERISTICS OF T CELLS

3522
03:07:07,340 --> 03:07:10,177
 THAT HAVE WITHIN THOUGHT TO

3523
03:07:10,177 --> 03:07:18,919
 BE -- BEEN THOUGHT TO BE 

3524
03:07:18,919 --> 03:07:23,290
 IMPOSED WITH THE NTK AND THERE

3525
03:07:23,290 --> 03:07:25,292
 IS SOME EARLY SUGGESTIONS IN A

3526
03:07:25,292 --> 03:07:30,931
 PAPER THAT IT IS RESTRICTED

3527
03:07:30,931 --> 03:07:35,769
 WITH THE INFECTED T CELL AND

3528
03:07:35,769 --> 03:07:38,171
 WHAT BRINGS LCK INTO THE

3529
03:07:38,171 --> 03:07:40,774
 COMPLEX OF THE LAB AND

3530
03:07:40,774 --> 03:07:42,242
 CORRELATION, THAT SIGNAL IS

3531
03:07:42,242 --> 03:07:46,746
 NOT GENERATED WHEN THE T CELL

3532
03:07:46,746 --> 03:07:50,784
 IS RECOGNIZED BY THE LIGAND.

3533
03:07:50,784 --> 03:07:52,919
 AND THEN EARLY LAST YEAR WE

3534
03:07:52,919 --> 03:07:58,091
 WERE LOOKING AT THE

3535
03:07:58,091 --> 03:08:00,861
 ASSOCIATION OF POLICY LATER

3536
03:08:00,861 --> 03:08:03,630
 AND WHAT WE KNOW IS THAT IN

3537
03:08:03,630 --> 03:08:05,832
 ALMOST ALL CASES, HERE SHOWING

3538
03:08:05,832 --> 03:08:07,033
 THE CLASS 1 RECOGNITION, THIS

3539
03:08:07,033 --> 03:08:11,404
 IS A BIRDS EYE VIEW OF SORT OF

3540
03:08:11,404 --> 03:08:12,439
 INTERACTION WHERE CRYSTAL

3541
03:08:12,439 --> 03:08:13,507
 STRUCTURES HAVE BEEN

3542
03:08:13,507 --> 03:08:16,243
 DETERMINED AND WHAT YOU CAN

3543
03:08:16,243 --> 03:08:18,712
 SEE IS ALMOST INVARIABLY, THE

3544
03:08:18,712 --> 03:08:21,348
 T CELL IS ON TOP OF THE ALPHA

3545
03:08:21,348 --> 03:08:25,919
 1 HELIX AND THE T CELL SITS

3546
03:08:25,919 --> 03:08:30,023
 OVER THE TOP OF THE MHC ALPHA

3547
03:08:30,023 --> 03:08:30,724
 2 HELIX.

3548
03:08:30,724 --> 03:08:34,127
 SO WHAT WE SHOWED A COUPLE OF

3549
03:08:34,127 --> 03:08:37,330
 YEARS AGO IS THE CURRENT

3550
03:08:37,330 --> 03:08:39,566
 ASSOCIATION WITH LCK WAS

3551
03:08:39,566 --> 03:08:41,968
 REALLY CRITICAL FOR PREVENTING

3552
03:08:41,968 --> 03:08:43,737
 THE UNCONVENTIONAL ACTION FROM

3553
03:08:43,737 --> 03:08:46,873
 GENERATING A SIGNAL SO WE KNOW

3554
03:08:46,873 --> 03:08:48,475
 THOSE T CELL RECEPTORS COULD

3555
03:08:48,475 --> 03:08:50,477
 NOT BE DRAWN INTO THE IMMUNE

3556
03:08:50,477 --> 03:08:52,145
 RESPONSE AND WE SHOWED -- SO I

3557
03:08:52,145 --> 03:08:54,414
 WILL SHOW YOU THIS BRIEFLY HOW

3558
03:08:54,414 --> 03:08:55,148
 WE SHOWED THAT.

3559
03:08:55,148 --> 03:09:01,087
 SO THIS IS JUST THE SYSTEM SET

3560
03:09:01,087 --> 03:09:05,358
 UP WHERE WOULD YOU HAVE THE

3561
03:09:05,358 --> 03:09:09,129
 DATA WITH THE FUSION PROTEIN

3562
03:09:09,129 --> 03:09:12,332
 AND WE GET A CLEAN THREAT

3563
03:09:12,332 --> 03:09:14,267
 SIGNAL AND WHAT WE DID WAS

3564
03:09:14,267 --> 03:09:23,076
 LOOK AT SORT OF THE GENERATION

3565
03:09:23,076 --> 03:09:25,679
 OF SIGNALING ACROSS A RANGE OF

3566
03:09:25,679 --> 03:09:28,014
 I FINNY SHOWN HERE AS A PLUS

3567
03:09:28,014 --> 03:09:30,383
 SIGN AND QUICKLY TO SUMMARIZE,

3568
03:09:30,383 --> 03:09:32,586
 THIS IS NO PEPTIDE ON THE LEFT

3569
03:09:32,586 --> 03:09:36,356
 AND THE RIGHT AND WHAT WE

3570
03:09:36,356 --> 03:09:38,425
 FOUND IS WE ARE SIGNALING

3571
03:09:38,425 --> 03:09:41,494
 THREAT WHEN THE T CELL IS

3572
03:09:41,494 --> 03:09:44,698
 DOCKED IN A CERTAIN LOCATION

3573
03:09:44,698 --> 03:09:49,836
 AND NOT A REVERSED LOCATION

3574
03:09:49,836 --> 03:09:55,008
 AND COULD NOT BRING THE LCK IN

3575
03:09:55,008 --> 03:09:57,377
 THE PROCESS. 

3576
03:09:57,377 --> 03:09:59,479
 SO THEN IF WE BRING IN THE LCK

3577
03:09:59,479 --> 03:10:03,149
 WE CAN GET IT IN

3578
03:10:03,149 --> 03:10:04,017
 UNCONVENTIONAL FORMATS AND

3579
03:10:04,017 --> 03:10:05,719
 THAT IS WHAT IS SHOWN HERE IN

3580
03:10:05,719 --> 03:10:07,721
 THE BLACK HERE.

3581
03:10:07,721 --> 03:10:11,358
 SO IF WE STIMULATE WITH

3582
03:10:11,358 --> 03:10:15,495
 PEPTIDES AND AS I MENTIONED,

3583
03:10:15,495 --> 03:10:18,598
 WE CAN GET SIGNALING IN THE

3584
03:10:18,598 --> 03:10:20,667
 REVERSION AND NOT THE TCI SO

3585
03:10:20,667 --> 03:10:27,507
 OF COURSE WE HURT THE

3586
03:10:27,507 --> 03:10:28,942
 CANONICAL T CELERY SEPTEMBER

3587
03:10:28,942 --> 03:10:32,112
 TORE AND IF WE LEAVE THE T8 IN

3588
03:10:32,112 --> 03:10:37,550
 THESE CELLS SO THEY CAN STILL

3589
03:10:37,550 --> 03:10:41,221
 LIVE UP TO THE INTERACTION, WE

3590
03:10:41,221 --> 03:10:43,556
 SEE ROBUST SIGNALING BY THE

3591
03:10:43,556 --> 03:10:44,524
 TCR.

3592
03:10:44,524 --> 03:10:47,861
 SO THESE ARE TWO SORT OF

3593
03:10:47,861 --> 03:10:50,330
 PARADIGMS THAT ARE TO BE

3594
03:10:50,330 --> 03:10:51,097
 IMPOSED WITH LCK.

3595
03:10:51,097 --> 03:10:52,599
 SO I BELIEVE THEY HAVE BEEN

3596
03:10:52,599 --> 03:10:56,836
 ASSESSED IN BOTH CASES USING

3597
03:10:56,836 --> 03:10:59,773
 INDIVIDUAL TCRS OR IN VITRO

3598
03:10:59,773 --> 03:11:02,375
 SYSTEMS WITH A LIMITED NUMBER

3599
03:11:02,375 --> 03:11:04,878
 OF TCRS SO THAT REALLY RAISES

3600
03:11:04,878 --> 03:11:10,650
 THE QUESTION FOR US HOW DOES 

3601
03:11:10,650 --> 03:11:14,688
 THIS ASSOCIATION IMPACT ON THE

3602
03:11:14,688 --> 03:11:19,125
 DOCKING POLE LATER OF INFECTED

3603
03:11:19,125 --> 03:11:29,502
 T CELL RESPONSES.

3604
03:11:32,906 --> 03:11:35,909
 SO WE HAVE THIS IMPACT IN THE

3605
03:11:35,909 --> 03:11:37,077
 MEMBRANE OF ASSOCIATION.

3606
03:11:37,077 --> 03:11:38,445
 AND QUICKLY TO GO OVER THIS

3607
03:11:38,445 --> 03:11:39,813
 BECAUSE IT HAS BEEN SHOWN

3608
03:11:39,813 --> 03:11:43,416
 BEFORE, WHAT WE FOUND IN THE

3609
03:11:43,416 --> 03:11:50,757
 THYMUS IS A SIGNIFICANT CD4

3610
03:11:50,757 --> 03:11:54,260
 BUT REAL KNOW NO CHANGE IN CD8

3611
03:11:54,260 --> 03:11:58,431
 NUMBERS AND JUST AS AN ASIDE,

3612
03:11:58,431 --> 03:11:59,699
 SORRY, THIS PHENOTYPE IS SHOWN

3613
03:11:59,699 --> 03:12:05,905
 IN THE PERIPHERY AND CD4 IS NO

3614
03:12:05,905 --> 03:12:08,007
 DIFFERENT THAN CD8T CELL

3615
03:12:08,007 --> 03:12:09,809
 NUMBERS AND IN TRUE NAIVE,

3616
03:12:09,809 --> 03:12:11,611
 THERE IS A VIRTUAL INCREASE IN

3617
03:12:11,611 --> 03:12:14,714
 THE POPULATION, THIS IS AN

3618
03:12:14,714 --> 03:12:16,983
 ANTIGEN INCREASE IN POPULATION

3619
03:12:16,983 --> 03:12:21,054
 OF T CELLS FORMED IN THE

3620
03:12:21,054 --> 03:12:22,021
 THYMUS AND DEVELOPMENT

3621
03:12:22,021 --> 03:12:23,690
 COMPLETED IN THE PERIPHERY.

3622
03:12:23,690 --> 03:12:28,695
 SO WE FOUND THAT WAS DUE TO AN

3623
03:12:28,695 --> 03:12:30,530
 INCREASE IN IL4 AND PROBABLY

3624
03:12:30,530 --> 03:12:32,332
 BECAUSE OF INCREASE IN T CELL

3625
03:12:32,332 --> 03:12:34,501
 NUMBERS AND I WILL COME BACK

3626
03:12:34,501 --> 03:12:36,169
 TO THIS A LITTLE LATER IN THE

3627
03:12:36,169 --> 03:12:36,870
 TALK.

3628
03:12:36,870 --> 03:12:40,106
 SO THE FIRST THING WE WANTED

3629
03:12:40,106 --> 03:12:50,683
 TO DO WAS ACTUALLY CHALLENGE

3630
03:12:50,683 --> 03:12:52,685
 THESE THAT ARE REDUCED AND

3631
03:12:52,685 --> 03:12:54,988
 THIS IS WHAT WE FOUND.

3632
03:12:54,988 --> 03:12:57,991
 YOU CAN SEE HERE THERE IS

3633
03:12:57,991 --> 03:13:01,828
 ABSOLUTELY NO DIFFERENCE IN

3634
03:13:01,828 --> 03:13:05,598
 THE MAG TODAY TO -- MAGNITUDE

3635
03:13:05,598 --> 03:13:10,036
 OF THE RESPONSE BETWEEN THE

3636
03:13:10,036 --> 03:13:16,142
 LCK FREE MICE IN CD8T CELL

3637
03:13:16,142 --> 03:13:18,311
 RECEPTORS AS FAR AS WE COULD

3638
03:13:18,311 --> 03:13:20,113
 MEASURE AND THERE WERE ONLY

3639
03:13:20,113 --> 03:13:22,515
 MINOR DIFFERENCES SO LOOKING

3640
03:13:22,515 --> 03:13:29,489
 AT POSSIBLY A SLIGHT DROP IN

3641
03:13:29,489 --> 03:13:33,827
 CELLS THAT REDUCE

3642
03:13:33,827 --> 03:13:37,530
 MITOCHONDRIAL RESPONSE BUT

3643
03:13:37,530 --> 03:13:40,400
 ROBUST RESTRICTED RESPONSE TO

3644
03:13:40,400 --> 03:13:40,767
 INFECTION.

3645
03:13:40,767 --> 03:13:50,076
 AND BY CONTRAST LOOKING AT THE

3646
03:13:50,076 --> 03:13:52,212
 TCRAVIDITY AND T CELL

3647
03:13:52,212 --> 03:13:54,614
 RESPONSE, THIS IS THE CYTOKINE

3648
03:13:54,614 --> 03:13:59,886
 PRODUCTION AND YOU CAN SEE

3649
03:13:59,886 --> 03:14:02,789
 HERE YOU HAVE THE T CELL ABLE

3650
03:14:02,789 --> 03:14:05,124
 TO RESPOND IN THE LCK AND THIS

3651
03:14:05,124 --> 03:14:10,697
 IS OBSERVED FOR A SECOND HERE

3652
03:14:10,697 --> 03:14:14,100
 WITH IHA211 AND THIS IS JUST

3653
03:14:14,100 --> 03:14:15,568
 INTRODUCED AFTER STIMULATION.

3654
03:14:15,568 --> 03:14:17,170
 CYTOKINE PRODUCTION WAS

3655
03:14:17,170 --> 03:14:20,807
 RELATIVELY NORMAL SO IT COULD

3656
03:14:20,807 --> 03:14:26,279
 RESPOND GIVEN THE RESPECT TOY,

3657
03:14:26,279 --> 03:14:27,213
 RESPONDED -- REPERTOIRE,

3658
03:14:27,213 --> 03:14:29,749
 RESPONDED REASONABLY WELL.

3659
03:14:29,749 --> 03:14:33,853
 SO THEN WE INFECTED THE MICE

3660
03:14:33,853 --> 03:14:43,463
 AT DAY 10 AND FOUND THE

3661
03:14:43,463 --> 03:14:47,333
 TETRAMER WITH THE LCK CELLS

3662
03:14:47,333 --> 03:14:51,537
 AND DID TARGETED SCRNA AND THE

3663
03:14:51,537 --> 03:14:53,239
 SEQUENCING SHOWS VERY MINIMAL

3664
03:14:53,239 --> 03:14:56,743
 CHANGES IN THE EFFECTOR T CELL

3665
03:14:56,743 --> 03:14:57,310
 RESPONSE.

3666
03:14:57,310 --> 03:15:00,246
 THE BIGGEST DIFFERENCE YOU CAN

3667
03:15:00,246 --> 03:15:02,348
 SEE HERE, THAT WAS A

3668
03:15:02,348 --> 03:15:04,417
 SUBSTANTIAL DROP IN A

3669
03:15:04,417 --> 03:15:05,752
 SUBPOPULATION IN THE VIRTUAL

3670
03:15:05,752 --> 03:15:08,154
 MEMORY OF T CELLS AND THAT IS

3671
03:15:08,154 --> 03:15:10,290
 QUANTITATED OVER HERE SO

3672
03:15:10,290 --> 03:15:11,424
 ESSENTIALLY THE VIRTUAL MEMORY

3673
03:15:11,424 --> 03:15:13,793
 T CELLS SHOWN IN THE RED, DARK

3674
03:15:13,793 --> 03:15:15,895
 GREEN AND LIGHT GREEN AND WHAT

3675
03:15:15,895 --> 03:15:21,067
 WE FOUND IS THEY WERE MISSING

3676
03:15:21,067 --> 03:15:24,003
 OR RATHER MIDDLE EAST --

3677
03:15:24,003 --> 03:15:26,940
 DEFICIENT IN THESE SMALL

3678
03:15:26,940 --> 03:15:32,078
 MEMORY RESPONSES FOR LCK

3679
03:15:32,078 --> 03:15:32,645
 RECEPTORS.

3680
03:15:32,645 --> 03:15:33,780
 OTHERWISE, THERE WAS LITTLE

3681
03:15:33,780 --> 03:15:35,348
 DIFFERENCE, ONLY A SLIGHT

3682
03:15:35,348 --> 03:15:38,084
 REDUCTION HERE CLASSIFIED AS A

3683
03:15:38,084 --> 03:15:42,255
 TH1 SUBSET BUT IN FACT AN

3684
03:15:42,255 --> 03:15:50,830
 INSPECTION OF THE EXPRESSED

3685
03:15:50,830 --> 03:15:53,399
 EXODE, WE SAW K2 EXPRESSED IN

3686
03:15:53,399 --> 03:15:56,703
 THESE MICE SO VERY MINIMAL

3687
03:15:56,703 --> 03:15:58,404
 ACTIVATION IN THESE T CELL

3688
03:15:58,404 --> 03:15:58,938
 POPULATION.

3689
03:15:58,938 --> 03:16:07,580
 SO THEN WE LOOKED AT THE CDA

3690
03:16:07,580 --> 03:16:10,450
 POSITIVE REPERTOIRE AND HERE

3691
03:16:10,450 --> 03:16:15,388
 SHOWING THE IMMUNE REPERTOIRE

3692
03:16:15,388 --> 03:16:22,195
 AND THAT IS SHOWING THE ALPHA

3693
03:16:22,195 --> 03:16:25,098
 B AND ALPHA J SO THESE WILD

3694
03:16:25,098 --> 03:16:27,734
 TYPES HAVE BEEN REALLY WELL

3695
03:16:27,734 --> 03:16:29,002
 CHARACTERIZED BY US AND OTHERS

3696
03:16:29,002 --> 03:16:32,505
 OVER THE YEARS AND WHAT WE

3697
03:16:32,505 --> 03:16:37,310
 SHOW IS A DBNP DOMINANCE

3698
03:16:37,310 --> 03:16:40,013
 PAIRED WITH IL16 AND THESE

3699
03:16:40,013 --> 03:16:44,484
 CELLS HAVE SELECTIVELY 

3700
03:16:44,484 --> 03:16:45,618
 EXPANDED AFTER INFECTION WITH

3701
03:16:45,618 --> 03:16:45,985
 AFFINITY.

3702
03:16:45,985 --> 03:16:49,022
 AND WHAT YOU CAN SEE IF YOU

3703
03:16:49,022 --> 03:16:54,627
 COMPARE THE WILD TYPES WITH 

3704
03:16:54,627 --> 03:17:00,133
 LC3'S, THE LC3'S REALLY SHOW 

3705
03:17:00,133 --> 03:17:01,701
 THE HIGH RESPONSE.

3706
03:17:01,701 --> 03:17:08,875
 THESE TALES OF MORE TCI

3707
03:17:08,875 --> 03:17:10,009
 ALGORITHM TO QUOTE THE

3708
03:17:10,009 --> 03:17:11,944
 SIMILARITY BETWEEN THE

3709
03:17:11,944 --> 03:17:13,012
 PHENOTYPES, WHAT IS SHOWN HERE

3710
03:17:13,012 --> 03:17:16,983
 IS THE CLUSTER REALLY DEFINED

3711
03:17:16,983 --> 03:17:20,686
 BY THESE SO WE KIND OF PULLED

3712
03:17:20,686 --> 03:17:23,890
 ON THE HEADS OF THESE AND THEN

3713
03:17:23,890 --> 03:17:28,061
 THE TAILS HAVE MORE RECEPTIVE

3714
03:17:28,061 --> 03:17:28,761
 T CELL RECEPTORS AND YOU CAN

3715
03:17:28,761 --> 03:17:39,338
 SEE THEY ARE REALLY FOCUSED ON

3716
03:17:47,313 --> 03:17:47,980
 THE CLUSTERS.

3717
03:17:47,980 --> 03:17:50,917
 SO ON THE LEFT OF THE MORE

3718
03:17:50,917 --> 03:17:53,686
 CLUSTER TCR, YOU CAN SEE A LOT

3719
03:17:53,686 --> 03:17:56,089
 MORE OF THE REPERTOIRE IS

3720
03:17:56,089 --> 03:17:58,558
 DOMINATED BY THE CLUSTERS AND

3721
03:17:58,558 --> 03:17:59,992
 THAT IS LESS TRUE OF THE WILD

3722
03:17:59,992 --> 03:18:03,229
 CARD THAT HAS MORE OF THESE

3723
03:18:03,229 --> 03:18:03,529
 TALES.

3724
03:18:03,529 --> 03:18:06,199
 SO WE WANTED TO COMPARE IS

3725
03:18:06,199 --> 03:18:09,035
 THIS A SHIFT THAT IS OCCURRING

3726
03:18:09,035 --> 03:18:10,636
 UPON SELECTION OF THE

3727
03:18:10,636 --> 03:18:12,305
 REPERTOIRE OR IS THERE AN

3728
03:18:12,305 --> 03:18:14,540
 ALTERATION IN THE NAIVE

3729
03:18:14,540 --> 03:18:16,142
 REPERTOIRE?

3730
03:18:16,142 --> 03:18:21,447
 SO WE LOOKED AT NAIVE, NP

3731
03:18:21,447 --> 03:18:23,282
 CELLS FROM THE REPERTOIRE AND

3732
03:18:23,282 --> 03:18:27,286
 THIS IS TRICKY BECAUSE THEY

3733
03:18:27,286 --> 03:18:29,055
 ONLY GET AROUND 5-20 CELLS IN

3734
03:18:29,055 --> 03:18:30,223
 THE INDIVIDUAL MOUSE AND WHAT

3735
03:18:30,223 --> 03:18:32,692
 YOU CAN SEE IS THIS

3736
03:18:32,692 --> 03:18:35,194
 PREFERENCE, THIS SORT OF

3737
03:18:35,194 --> 03:18:37,964
 DOMINANCE IS PREEXISTENT IN

3738
03:18:37,964 --> 03:18:38,698
 THESE NAIVE REPERTOIRE.

3739
03:18:38,698 --> 03:18:40,933
 SO HERE WE HAVE THE WILD FIVE

3740
03:18:40,933 --> 03:18:45,338
 REPERTOIRE WHICH IS MUCH MORE

3741
03:18:45,338 --> 03:18:47,773
 DIVERSE AND THE NAIVE

3742
03:18:47,773 --> 03:18:49,575
 REPERTOIRE WHICH IS ALREADY

3743
03:18:49,575 --> 03:18:50,076
 MORE RESTRICTIVE.

3744
03:18:50,076 --> 03:18:53,079
 AND YOU CAN SEE THAT SORT OF

3745
03:18:53,079 --> 03:18:55,114
 STRIKE IN HERE WHERE WE'RE

3746
03:18:55,114 --> 03:18:57,517
 ALREADY SEEING CLUSTER SORT OF

3747
03:18:57,517 --> 03:19:01,354
 DOMINATING IN THE NAIVE

3748
03:19:01,354 --> 03:19:03,322
 REPRESENT TORE -- REPERTOIRE.

3749
03:19:03,322 --> 03:19:06,225
 SO THIS IS ALSO TRUE, THIS IS

3750
03:19:06,225 --> 03:19:09,729
 THE PA REPERTOIRE, WE SEE THIS

3751
03:19:09,729 --> 03:19:14,467
 DOMINANCE IN THE WILD TYPE AND

3752
03:19:14,467 --> 03:19:19,805
 NOT QUITE THAT SENSE IN THE

3753
03:19:19,805 --> 03:19:22,642
 NIGH NAIVE REPERTOIRE WHICH IS

3754
03:19:22,642 --> 03:19:27,713
 MUCH MORE DIVERSE ALTHOUGH THE

3755
03:19:27,713 --> 03:19:31,684
 DBPA IS MORE PRESENT BUT

3756
03:19:31,684 --> 03:19:32,718
 EXACERBATED IN THE FREE

3757
03:19:32,718 --> 03:19:36,155
 REPERTOIRE AND THAT IS THE

3758
03:19:36,155 --> 03:19:38,858
 CASE HERE WHERE THIS CLUSTER

3759
03:19:38,858 --> 03:19:43,196
 IS SHOWN HERE AND RATHER

3760
03:19:43,196 --> 03:19:44,897
 DEVOID OF THESE TALES.

3761
03:19:44,897 --> 03:19:45,998
 SO AS A CONSEQUENCE OF THESE

3762
03:19:45,998 --> 03:19:48,668
 WHAT I WANT TO POINT OUT IS WE

3763
03:19:48,668 --> 03:19:50,136
 SEE A NARROWING OF THE

3764
03:19:50,136 --> 03:19:50,603
 REPERTOIRE.

3765
03:19:50,603 --> 03:19:52,972
 SO WE GO FROM A MORE DIVERSE

3766
03:19:52,972 --> 03:19:54,807
 REPERTOIRE TO A MORE NARROW

3767
03:19:54,807 --> 03:19:59,712
 REPERTOIRE AND THAT IS TRUE OF

3768
03:19:59,712 --> 03:20:03,816
 THE NP AND NAIVE REPERTOIRE

3769
03:20:03,816 --> 03:20:13,226
 AND WE SEE THE PATH FOR 

3770
03:20:13,226 --> 03:20:15,861
 SELECTION IS REDUCED CAPACITY

3771
03:20:15,861 --> 03:20:17,797
 FOR IMMUNE SELECTION AND THESE

3772
03:20:17,797 --> 03:20:19,031
 ARE INDIVIDUAL SELECTIONS OF

3773
03:20:19,031 --> 03:20:22,401
 INDIVIDUAL CLIENTS SO YOU CAN

3774
03:20:22,401 --> 03:20:25,271
 SEE WHILE WE ARE STILL GETTING

3775
03:20:25,271 --> 03:20:33,079
 SOME SELECTION, THE CAPACITY 

3776
03:20:33,079 --> 03:20:37,483
 IS LESS DOMINANT IN THE NAIVE

3777
03:20:37,483 --> 03:20:38,117
 VERSUS THE PA.

3778
03:20:38,117 --> 03:20:41,187
 SO THIS IS THE COLONIZATION OF

3779
03:20:41,187 --> 03:20:43,155
 THE NUMBER OF CELLS IN THE

3780
03:20:43,155 --> 03:20:44,557
 REPERTOIRE WHICH WE MIGHT

3781
03:20:44,557 --> 03:20:46,192
 EXPECT IS UNCHANGED BECAUSE

3782
03:20:46,192 --> 03:20:50,930
 THE TOTAL NUMBER IN THE CD8 IS

3783
03:20:50,930 --> 03:20:52,999
 UNCHANGED BUT THERE APPEARS TO

3784
03:20:52,999 --> 03:20:58,904
 BE AN AFFINITY ALREADY IN THE 

3785
03:20:58,904 --> 03:21:03,876
 LCK FREE VERSUS THE TCRMHC.

3786
03:21:03,876 --> 03:21:06,746
 SO THIS IS THE DISTANCE

3787
03:21:06,746 --> 03:21:07,713
 MEASUREMENT SHOWING THE

3788
03:21:07,713 --> 03:21:10,650
 DISTANCE FROM THE NAIVE TO THE

3789
03:21:10,650 --> 03:21:12,184
 IMMUNE REPERTOIRE BECAUSE

3790
03:21:12,184 --> 03:21:15,288
 WE'RE SEEING SELECTION OF THIS

3791
03:21:15,288 --> 03:21:17,657
 DOMINANT CLUSTER OF TCR SO

3792
03:21:17,657 --> 03:21:18,591
 THIS REDUCES TYPICALLY AND

3793
03:21:18,591 --> 03:21:21,627
 THAT IS TRUE FOR BOTH N &
PA

3794
03:21:21,627 --> 03:21:23,663
 BUT WE CAN SEE WE ARE NOT

3795
03:21:23,663 --> 03:21:25,931
 SEEING THAT NARROWING OR THAT

3796
03:21:25,931 --> 03:21:35,508
 SORT OF REDUCTION IN DISTANCE 

3797
03:21:35,508 --> 03:21:39,011
 IN THE LCK BECAUSE IT HAS THIS

3798
03:21:39,011 --> 03:21:39,545
 LIMITED REPERTOIRE.

3799
03:21:39,545 --> 03:21:42,014
 SO THIS IS A TERRIBLE SLIDE

3800
03:21:42,014 --> 03:21:43,949
 BUT I WANTED TO USE IT TO

3801
03:21:43,949 --> 03:21:44,784
 RAISE THE QUESTION BECAUSE

3802
03:21:44,784 --> 03:21:47,286
 THIS IS THE QUESTION WE WENT

3803
03:21:47,286 --> 03:21:49,422
 INTO THESE EXPERIMENTS FOR AND

3804
03:21:49,422 --> 03:21:51,757
 STILL HAVEN'T QUITE ANSWERED

3805
03:21:51,757 --> 03:21:52,758
 IT.

3806
03:21:52,758 --> 03:22:00,633
 AND THE HYPOTHESIS WAS T CELLS

3807
03:22:00,633 --> 03:22:03,235
 WITH DOCKING ORIENTATION

3808
03:22:03,235 --> 03:22:07,673
 SHOULD BE ABLE TO PREVENT A

3809
03:22:07,673 --> 03:22:10,743
 RESPONSE WITH LCK ESPECIALLY

3810
03:22:10,743 --> 03:22:14,947
 WHAT WE SHOWED IN SREUT VITRO

3811
03:22:14,947 --> 03:22:16,282
 SO IT MAY HAVE AROUND A

3812
03:22:16,282 --> 03:22:19,885
 QUARTER OF THE NAIVE

3813
03:22:19,885 --> 03:22:21,387
 REPERTOIRE AND VERY INFREQUENT

3814
03:22:21,387 --> 03:22:23,155
 WITH THE IMMUNE REPERTOIRE

3815
03:22:23,155 --> 03:22:26,959
 BECAUSE THEY CAN'T GET INTO

3816
03:22:26,959 --> 03:22:29,295
 THE REPERTOIRE.

3817
03:22:29,295 --> 03:22:32,465
 SO IN THE DNP, I AM NOT

3818
03:22:32,465 --> 03:22:35,101
 SHOWING THIS HERE BUT WE KNOW

3819
03:22:35,101 --> 03:22:39,071
 THEY HAVE A CANONICAL

3820
03:22:39,071 --> 03:22:41,407
 ORIENTATION SO THE DOCKING IS

3821
03:22:41,407 --> 03:22:45,244
 IRRELEVANT IN THE THY MUS SO

3822
03:22:45,244 --> 03:22:49,548
 WE SEE THE SIMULATION OF THE T

3823
03:22:49,548 --> 03:22:53,085
 CELLS IN THE NAIVE REPERTOIRE

3824
03:22:53,085 --> 03:22:54,653
 BUT IN THE IMMUNE REPERTOIRE,

3825
03:22:54,653 --> 03:23:02,695
 WE ARE NOT SEEING RECORRUPT IN

3826
03:23:02,695 --> 03:23:06,499
 THE TCR OR THE NAIVE LCK AND

3827
03:23:06,499 --> 03:23:08,334
 IT IS POSSIBLE THAT THEY ARE

3828
03:23:08,334 --> 03:23:09,802
 ACTIVATING THE IMMUNE PROCESS

3829
03:23:09,802 --> 03:23:14,507
 AND WHAT WE'RE DOING IS 

3830
03:23:14,507 --> 03:23:17,009
 EXPRESSING THESE DOCKERS IN

3831
03:23:17,009 --> 03:23:19,678
 THE CONTEXT OF A LCK

3832
03:23:19,678 --> 03:23:20,813
 BACKGROUND IN ORDER TO ANSWER

3833
03:23:20,813 --> 03:23:22,415
 THE QUESTION WHERE THE

3834
03:23:22,415 --> 03:23:24,250
 ASSOCIATION WILL OCCUR THAT

3835
03:23:24,250 --> 03:23:27,887
 CAN ALLOW THESE

3836
03:23:27,887 --> 03:23:30,022
 UNCONVENTIONALT TTCRS TO BE

3837
03:23:30,022 --> 03:23:31,290
 RECRUITED IN THE IMMUNE

3838
03:23:31,290 --> 03:23:32,291
 RESPONSE.

3839
03:23:32,291 --> 03:23:35,127
 AND SO THE ONE FINAL THING I

3840
03:23:35,127 --> 03:23:40,666
 WANTED TO MENTION IS IN THIS

3841
03:23:40,666 --> 03:23:42,601
 STIMULATION WHEN WE ARE

3842
03:23:42,601 --> 03:23:46,305
 INFECTING THE T CELLS WITH

3843
03:23:46,305 --> 03:23:47,206
 NEUROPEPTIDES, THEY CLUSTER

3844
03:23:47,206 --> 03:23:52,711
 AND THAT IS SHOWN HERE FOR THE

3845
03:23:52,711 --> 03:23:55,581
 TWO DIFFERENT CLASS 2 PEPTIDES

3846
03:23:55,581 --> 03:23:57,249
 AND THESE WERE.

3847
03:23:57,249 --> 03:23:58,584
 >> Genny: WIN CLASS 2

3848
03:23:58,584 --> 03:24:00,820
 RESPONSES, LOW FREQUENT SEE OF

3849
03:24:00,820 --> 03:24:05,090
 COURSE BUT ENRICHED WITH CLASS

3850
03:24:05,090 --> 03:24:08,494
 2TETRAMINE, YOU CAN SEE THIS

3851
03:24:08,494 --> 03:24:12,731
 IS GENUINE CLASS 2TETRAMINE

3852
03:24:12,731 --> 03:24:14,934
 STAINING, IT IS IMPORTANT TO

3853
03:24:14,934 --> 03:24:18,103
 NOTE THAT THEY CLEARLY

3854
03:24:18,103 --> 03:24:22,541
 EXPANDED AFTER INFECTION, WE 

3855
03:24:22,541 --> 03:24:31,717
 REEXPRESSED THEM AND THEY CAN

3856
03:24:31,717 --> 03:24:41,193
 BE IMAGED WITH THE HELP OF PR

3857
03:24:41,193 --> 03:24:42,828
 IYANKA CHAURASIA AND OTHERS.

3858
03:24:42,828 --> 03:24:49,201
 BUT THEY DID HAVE A HIGH

3859
03:24:49,201 --> 03:24:50,703
 AFFINITY.

3860
03:24:50,703 --> 03:24:52,271
 INTERESTINGLY, TWO TCRS FROM

3861
03:24:52,271 --> 03:24:59,912
 TWO DIFFERENT MICE HAD VERY

3862
03:24:59,912 --> 03:25:07,853
 SIMILAR CHARACTERISTICS FOR 

3863
03:25:07,853 --> 03:25:11,824
 COR5 AND CDR -- TCR2 AND WE

3864
03:25:11,824 --> 03:25:13,592
 ARE NOT SURE THE

3865
03:25:13,592 --> 03:25:14,927
 CHARACTERISTICS THAT ALLOW

3866
03:25:14,927 --> 03:25:15,561
 THAT.

3867
03:25:15,561 --> 03:25:22,635
 THE T CELLS ARE GENUINE TD 8T

3868
03:25:22,635 --> 03:25:27,106
 CELLS, THEY EXPRESS HIGHS AND 

3869
03:25:27,106 --> 03:25:31,744
 LOWS OF TH LCK AND ALSO

3870
03:25:31,744 --> 03:25:33,679
 ENZYMES WHICH I AM NOT SHOWING

3871
03:25:33,679 --> 03:25:35,748
 HERE AND APPEARS WHEN WE LOOK

3872
03:25:35,748 --> 03:25:39,552
 AT THE WILD TYPE REPERTOIRE,

3873
03:25:39,552 --> 03:25:42,521
 WE THOUGHT THIS WAS A

3874
03:25:42,521 --> 03:25:45,124
 REDIRECTION FROM THE CD4

3875
03:25:45,124 --> 03:25:49,194
 LINEAGE TO THE CD8 LINEAGE

3876
03:25:49,194 --> 03:25:55,067
 RATHER THAN AN EXPRESSION OF A

3877
03:25:55,067 --> 03:25:55,935
 REALLY ODD LINEAGE.

3878
03:25:55,935 --> 03:25:58,804
 BUT YOU CAN SEE IN THE

3879
03:25:58,804 --> 03:26:03,742
 BACKGROUND WHEN EXPRESSED ON A

3880
03:26:03,742 --> 03:26:05,811
 WILD TYPE BACKGROUND, IT

3881
03:26:05,811 --> 03:26:10,115
 EXPRESSED T CELLS BUT ON THE

3882
03:26:10,115 --> 03:26:14,286
 LCK FREE BACKGROUND, THEY ARE 

3883
03:26:14,286 --> 03:26:24,863
 ABLE TO FAVOR A LINEATION FOR

3884
03:26:29,902 --> 03:26:30,536
 MHCH RESTRICTED.

3885
03:26:30,536 --> 03:26:38,577
 SO THIS RESULTS IN A LOSS OF T

3886
03:26:38,577 --> 03:26:43,315
 CELLS EXPRESSING MODERATE MHC

3887
03:26:43,315 --> 03:26:44,383
 SPECIFIC CD4T CELLS, RESULTS

3888
03:26:44,383 --> 03:26:47,620
 IN LOSS OF T CELLS EXPRESSING

3889
03:26:47,620 --> 03:26:50,723
 LOW AND MODERATE AFFINITY OF

3890
03:26:50,723 --> 03:26:57,596
 TCRS AND IT REDUCES THE

3891
03:26:57,596 --> 03:26:59,565
 CAPACITY FOR IMMUNE SELECTION

3892
03:26:59,565 --> 03:27:02,067
 AND SELECTIVE RECRUITMENT OF

3893
03:27:02,067 --> 03:27:03,402
 HIGH AFFINITY T CELLS AND

3894
03:27:03,402 --> 03:27:09,808
 ALLOWS FOR THE LINEAGE 

3895
03:27:09,808 --> 03:27:11,510
 REDIRECTION OF MHCII

3896
03:27:11,510 --> 03:27:14,113
 RESTRICTED CELLS TO CD8T

3897
03:27:14,113 --> 03:27:14,847
 CELLS.

3898
03:27:14,847 --> 03:27:17,216
 SO WE KNOW FROM BUSH'S LOVELY

3899
03:27:17,216 --> 03:27:21,086
 PAPER THAT IT IS THIS TALE OF

3900
03:27:21,086 --> 03:27:24,156
 T CELL RECEPTORS THAT ARE NOT

3901
03:27:24,156 --> 03:27:27,393
 CRITICAL FOR THE VIRAL

3902
03:27:27,393 --> 03:27:30,863
 INFECTION OR ANT GENT BUT ARE

3903
03:27:30,863 --> 03:27:37,069
 CRITICAL FOR RECOGNITION OF

3904
03:27:37,069 --> 03:27:37,569
 VIRAL EXPRESSION.

3905
03:27:37,569 --> 03:27:43,409
 SO THIS IS JUST AN OBSERVATION

3906
03:27:43,409 --> 03:27:50,616
 TO SHOW THE MODEL OF T CELL

3907
03:27:50,616 --> 03:27:51,784
 EXPRESSION, WHETHER CLASS 1 OR

3908
03:27:51,784 --> 03:27:53,318
 CLASS 2 AFTER POSITIVE

3909
03:27:53,318 --> 03:27:57,256
 SELECTION WHEN THEY RECEIVE A

3910
03:27:57,256 --> 03:28:01,326
 SIGNAL, BOTH WILL TRANSIENTLY

3911
03:28:01,326 --> 03:28:04,263
 POPULATE TO CD8 AND IN THE

3912
03:28:04,263 --> 03:28:08,000
 ABSENCE OF CD8, IT WILL BECOME

3913
03:28:08,000 --> 03:28:09,168
 CD4 POSITIVE CELLS AND

3914
03:28:09,168 --> 03:28:13,038
 OTHERWISE IF THE SIGNAL IS

3915
03:28:13,038 --> 03:28:14,540
 INDUCED OR INTERRUPTED, IT

3916
03:28:14,540 --> 03:28:16,809
 WILL BECOME CD8 POSITIVE

3917
03:28:16,809 --> 03:28:17,109
 CELLS.

3918
03:28:17,109 --> 03:28:21,380
 SO WHAT I SHOULD HAVE

3919
03:28:21,380 --> 03:28:27,820
 MENTIONED IS WHERE WE KNOW AT 

3920
03:28:27,820 --> 03:28:33,358
 CD4, IT MAKES SENSE DURING

3921
03:28:33,358 --> 03:28:41,133
 POSITIVE LINEATION THE CD8 HAS

3922
03:28:41,133 --> 03:28:44,269
 INTERMEDIATE T CELLS AND ALSO

3923
03:28:44,269 --> 03:28:47,506
 LCK BINDS CD4 WITH HIGHER

3924
03:28:47,506 --> 03:28:49,775
 AFFINITY THAN CD8 AND I THINK

3925
03:28:49,775 --> 03:28:51,610
 IT ALLOWS T CELLS THAT

3926
03:28:51,610 --> 03:28:57,216
 OTHERWISE SHOULD HAVE GOTTEN A

3927
03:28:57,216 --> 03:28:58,350
 STRONGER SIGNAL BE DIRECTED

3928
03:28:58,350 --> 03:29:01,820
 DOWN THE PATHWAY TO CD8

3929
03:29:01,820 --> 03:29:02,521
 POSITIVE CELLS.

3930
03:29:02,521 --> 03:29:05,557
 SO THANK THE PEOPLE INVOLVED

3931
03:29:05,557 --> 03:29:08,994
 IN THIS WORK, THOSE INVOLVED

3932
03:29:08,994 --> 03:29:11,563
 WITH THE DOCKING STUDY, THE

3933
03:29:11,563 --> 03:29:14,266
 STUDENTS IN THE LAB SHOWN HERE

3934
03:29:14,266 --> 03:29:16,535
 HAVE DONE MUCH OF THIS WORK

3935
03:29:16,535 --> 03:29:19,972
 AND THIS HAS BEEN A GREAT

3936
03:29:19,972 --> 03:29:26,445
 COLLABORATION WITH STRUCTURAL

3937
03:29:26,445 --> 03:29:27,212
 BIOLOGIST JAMIE ROSSJOHN,

3938
03:29:27,212 --> 03:29:37,756
 THANK YOU AND I AM HAPPY TO 

3939
03:29:49,802 --> 03:29:52,237
 TAKE ANY QUESTIONS.

3940
03:29:52,237 --> 03:29:55,541
 >> SO A VERY NICE TALK
AND I

3941
03:29:55,541 --> 03:29:59,745
 THINK I HAVE SIGNAL FOR THIS

3942
03:29:59,745 --> 03:30:05,417
 SO TO COME OUT OF THIS, THIS

3943
03:30:05,417 --> 03:30:09,154
 FITS SUM PHAEUGSZ FROM DEVIN

3944
03:30:09,154 --> 03:30:13,625
 SEVERAL YEARS AGO IN WILD TYPE

3945
03:30:13,625 --> 03:30:14,359
 MOUSE --

3946
03:30:14,359 --> 03:30:15,661
 [INDISCERNIBLE]

3947
03:30:15,661 --> 03:30:18,897
 SO I THINK THIS IS -- THE IDEA

3948
03:30:18,897 --> 03:30:24,870
 IS FOR SOME REASON THIS ECO IS

3949
03:30:24,870 --> 03:30:27,906
 NOT AS STRONG AS IT SHOULD BE

3950
03:30:27,906 --> 03:30:31,176
 AND CAN BE SELF --

3951
03:30:31,176 --> 03:30:33,612
 [INDISCERNIBLE] 

3952
03:30:33,612 --> 03:30:42,888
 AND ALSO SEVERAL YEARS CD4

3953
03:30:42,888 --> 03:30:44,056
 EXPRESSED IN CD8 AND YOU CAN

3954
03:30:44,056 --> 03:30:45,057
 SEE THIS VERY WELL.

3955
03:30:45,057 --> 03:30:46,291
 AND THE OTHER THING I WOULD

3956
03:30:46,291 --> 03:30:53,365
 LIKE TO SAY IS IT APPEARS TO

3957
03:30:53,365 --> 03:30:56,134
 ME THAT THIS IS CONSISTENT

3958
03:30:56,134 --> 03:30:58,670
 WITH THE MODEL BECAUSE IN A

3959
03:30:58,670 --> 03:30:59,872
 SENSE --

3960
03:30:59,872 --> 03:31:00,339
 [INDISCERNIBLE]

3961
03:31:00,339 --> 03:31:05,410
 THERE IS NO CD4 AND CANNOT

3962
03:31:05,410 --> 03:31:09,381
 KEEP THE BARRIER FOR THIS

3963
03:31:09,381 --> 03:31:13,151
 IMAGE, JUST MY 2 CENTS.

3964
03:31:13,151 --> 03:31:14,753
 >> THANK YOU.

3965
03:31:14,753 --> 03:31:20,959
 >>  I WOULD NOT VARY THAT
FAR.

3966
03:31:20,959 --> 03:31:23,528
 >> REALLY INTERESTING,
THANK

3967
03:31:23,528 --> 03:31:23,896
 YOU.

3968
03:31:23,896 --> 03:31:28,834
 I AM CURIOUS WHETHER IN THE

3969
03:31:28,834 --> 03:31:35,874
 LCK3 MICE DOES IT STOP THE

3970
03:31:35,874 --> 03:31:37,743
 INTERPRETATION IN LCK45 AND

3971
03:31:37,743 --> 03:31:40,012
 WHAT DOES IT DO TO THEM?

3972
03:31:40,012 --> 03:31:42,714
 >> NOT THAT I AM AWARE.

3973
03:31:42,714 --> 03:31:44,650
 IIT ONLY AFFECTS THE

3974
03:31:44,650 --> 03:31:47,286
 ASSOCIATION OF CD4 AND CD8.

3975
03:31:47,286 --> 03:31:49,454
 I WILL HAVE A LOOK BUT I AM

3976
03:31:49,454 --> 03:31:53,959
 PRETTY SURE IT DOESN'T.

3977
03:31:53,959 --> 03:31:56,261
 >> SO WOULD YOU -- SO THE
WAY

3978
03:31:56,261 --> 03:32:02,267
 YOU -- AS I UNDERSTAND THE

3979
03:32:02,267 --> 03:32:04,069
 STORY, YOU HAVE THE FOUR ROWS

3980
03:32:04,069 --> 03:32:07,673
 NOW YOU THINK THE RESERIOUS

3981
03:32:07,673 --> 03:32:11,276
 ORIENTED T CELL RECEPTORS ARE

3982
03:32:11,276 --> 03:32:14,613
 ACTUALLY SELECTED BY COLLECTOR

3983
03:32:14,613 --> 03:32:15,013
 ORIENTATION.

3984
03:32:15,013 --> 03:32:17,783
 AND IF YOU THINK THE PRELCK

3985
03:32:17,783 --> 03:32:20,752
 WOULD ALLOW SIGNALING BY THOSE

3986
03:32:20,752 --> 03:32:24,356
 REVERSE OR KWREPBD TCR WOULD

3987
03:32:24,356 --> 03:32:26,725
 WE NOT HAVE EXPECTED TO SEE

3988
03:32:26,725 --> 03:32:29,628
 MORE OF THEM WITH THE PRELCK?

3989
03:32:29,628 --> 03:32:32,164
 I DON'T KNOW IF I MADE MYSELF

3990
03:32:32,164 --> 03:32:33,632
 CLEAR BUT --

3991
03:32:33,632 --> 03:32:34,333
 >>  YEAH, I THINK SO.

3992
03:32:34,333 --> 03:32:36,535
 SO YOU ARE SUGGESTING NOW THAT

3993
03:32:36,535 --> 03:32:40,238
 WE HAVE LIB RATED LCK, THAT

3994
03:32:40,238 --> 03:32:44,609
 MAY BE THEY CAN BE SHOWN IN

3995
03:32:44,609 --> 03:32:46,078
 THE REVERSE ORIENTATION.

3996
03:32:46,078 --> 03:32:48,447
 >> YES, AND MAYBE MANY
OTHERS

3997
03:32:48,447 --> 03:32:50,415
 IN THE SELECT REVERSE

3998
03:32:50,415 --> 03:32:51,049
 ORIENTATION --

3999
03:32:51,049 --> 03:32:55,120
 >> YES, I THINK IT MIGHT
BE 

4000
03:32:55,120 --> 03:32:55,687
 TWO DIFFERENT LCKS.

4001
03:32:55,687 --> 03:32:57,823
 I THINK MAYBE IS THERE EVEN

4002
03:32:57,823 --> 03:33:00,192
 THE PEPTIDES THAT CAN SELECT

4003
03:33:00,192 --> 03:33:03,895
 THESE TCRS WHEN THEY ARE IN A

4004
03:33:03,895 --> 03:33:04,429
 REVERSE ORIENTATION?

4005
03:33:04,429 --> 03:33:04,796
 >> RIGHT.

4006
03:33:04,796 --> 03:33:06,231
 >> I DON'T KNOW THAT THAT
IS

4007
03:33:06,231 --> 03:33:08,834
 EVEN, YOU KNOW, WHY WOULD WE

4008
03:33:08,834 --> 03:33:10,002
 NECESSARILY EXPECT THAT?

4009
03:33:10,002 --> 03:33:11,870
 AND SO I WASN'T SURPRISED TO

4010
03:33:11,870 --> 03:33:15,140
 SEE THAT THEY ARE EQUIVALENTLY

4011
03:33:15,140 --> 03:33:15,640
 REPRESENTED.

4012
03:33:15,640 --> 03:33:17,743
 SO JUST FOR CLARITY, WE KNOW

4013
03:33:17,743 --> 03:33:19,911
 OR WE THINK THEY ARE SELECTED

4014
03:33:19,911 --> 03:33:21,079
 IN AN ECONOMIC ORIENTATION

4015
03:33:21,079 --> 03:33:23,348
 BECAUSE WE MADE A MUTATION

4016
03:33:23,348 --> 03:33:29,121
 ACROSS A MOUSE THAT HAD A A89E

4017
03:33:29,121 --> 03:33:31,990
 AND THAT IS UNION UNIQUELY

4018
03:33:31,990 --> 03:33:34,292
 IMPORTANT FOR THE REVERSE

4019
03:33:34,292 --> 03:33:37,796
 DOCKING RECOGNITION AND NOT A

4020
03:33:37,796 --> 03:33:39,965
 CANONICAL RECOGNITION AND WE

4021
03:33:39,965 --> 03:33:43,068
 SAW NO IMPACT ON THOSE TO COME

4022
03:33:43,068 --> 03:33:43,702
 OUT.

4023
03:33:43,702 --> 03:33:46,104
 SO I THINK THOSE ITSELF ARE AN

4024
03:33:46,104 --> 03:33:50,776
 ACCIDENT BUT AN ACCIDENT THAT

4025
03:33:50,776 --> 03:33:51,243
 IS IDEOLOGICAL.

4026
03:33:51,243 --> 03:33:53,412
 I MEAN WE FOUND THEM IN MICE

4027
03:33:53,412 --> 03:33:58,750
 AND NOW IN HUMANS SO THE

4028
03:33:58,750 --> 03:34:01,520
 HYPOTHESIS IS THIS

4029
03:34:01,520 --> 03:34:03,422
 CENTRALIZATION HAS A WAY OF

4030
03:34:03,422 --> 03:34:06,291
 STOPPING IT FROM GETTING INTO

4031
03:34:06,291 --> 03:34:08,060
 THE MICE BECAUSE THEY

4032
03:34:08,060 --> 03:34:09,394
 SHOULDN'T BE THERE.

4033
03:34:09,394 --> 03:34:10,829
 >> OKAY, GREAT TALK.

4034
03:34:10,829 --> 03:34:11,696
 A RANDOM THOUGHT.

4035
03:34:11,696 --> 03:34:14,332
 I AM WONDERING WHETHER IN

4036
03:34:14,332 --> 03:34:16,201
 SITUATIONS WHERE CORECEPTOR

4037
03:34:16,201 --> 03:34:20,005
 AND LCK CAN'T BE UTILIZED,

4038
03:34:20,005 --> 03:34:22,774
 WHETHER AS ANOTHER CONSEQUENCE

4039
03:34:22,774 --> 03:34:24,976
 IS THE LACK OF MEDIATED

4040
03:34:24,976 --> 03:34:28,880
 TERMINATION OF THE SIGNAL FOR

4041
03:34:28,880 --> 03:34:31,083
 THE L.A. X WOULD BE RESISTANT

4042
03:34:31,083 --> 03:34:33,418
 AND THAT WOULD MEAN THE SIGNAL

4043
03:34:33,418 --> 03:34:35,787
 WOULD GO ON A LITTLE LONGER

4044
03:34:35,787 --> 03:34:37,289
 AND WHETHER THAT WOULD BE THE

4045
03:34:37,289 --> 03:34:41,460
 CASE AND IF IT HAS ANY

4046
03:34:41,460 --> 03:34:42,060
 DOWNSTREAM CONSEQUENCES?

4047
03:34:42,060 --> 03:34:42,427
 >> MAYBE.

4048
03:34:42,427 --> 03:34:48,467
 SO YOU ARE TALKING ABOUT JUST

4049
03:34:48,467 --> 03:34:52,170
 IN RECOGNITION OR ACTIVATION

4050
03:34:52,170 --> 03:34:53,672
 THAT OCCURS INDEPENDENT?

4051
03:34:53,672 --> 03:34:55,373
 >> OBVIOUSLY THERE ARE
EARLIER

4052
03:34:55,373 --> 03:34:57,809
 EVENTS BUT THERE ARE LATER

4053
03:34:57,809 --> 03:35:00,712
 EVENTS WHERE THEY ARE SO THERE

4054
03:35:00,712 --> 03:35:03,448
 IS A TEMPORAL TIME PERIOD.

4055
03:35:03,448 --> 03:35:10,655
 IF THOSE SIGNALS OF INHIBITOR

4056
03:35:10,655 --> 03:35:15,227
 RECEPTOR ARE INDEPENDENT?

4057
03:35:15,227 --> 03:35:15,694
 [INDISCERNIBLE]

4058
03:35:15,694 --> 03:35:20,365
 >> LAG 3 FUNCTIONS BY
KNOCKING

4059
03:35:20,365 --> 03:35:22,634
 OFF LCK AND THE INDEPENDENCE

4060
03:35:22,634 --> 03:35:26,638
 OF LCK WON'T BE ABLE TO

4061
03:35:26,638 --> 03:35:27,706
 TERMINATE -- .

4062
03:35:27,706 --> 03:35:30,408
 >> I MEAN IT IS ENTIRELY

4063
03:35:30,408 --> 03:35:31,877
 POSSIBLE.

4064
03:35:31,877 --> 03:35:33,078
 BUT LIKE THE CORECEPTORS, WHAT

4065
03:35:33,078 --> 03:35:34,913
 IS HAPPENING WITH THEM AND IS

4066
03:35:34,913 --> 03:35:37,749
 THIS WHY WE'RE FINDING OUGHT

4067
03:35:37,749 --> 03:35:43,421
 THESE WEIRD INNATE PCR'S THAT

4068
03:35:43,421 --> 03:35:44,723
 ARE CLUSTERED IN STRANGE WAYS

4069
03:35:44,723 --> 03:35:46,758
 BECAUSE THEY CAN DO WHATEVER

4070
03:35:46,758 --> 03:35:48,426
 THEY LIKE SO I AM LOOKING AT

4071
03:35:48,426 --> 03:35:48,727
 THAT.

4072
03:35:48,727 --> 03:35:50,762
 >>  I AM BEING TOLD WE
HAVE TO

4073
03:35:50,762 --> 03:35:58,403
 MOVE ON TO GET LUNCH SO I WILL

4074
03:35:58,403 --> 03:36:01,606
 DISCUSS THAT DURING LUNCH.

4075
03:36:01,606 --> 03:36:06,311
 THANK YOU.

4076
03:36:06,311 --> 03:36:15,453
 SO THE FINAL FIGURE AND 

4077
03:36:15,453 --> 03:36:17,255
 PRELUNCH SPEAKER IS LARRY

4078
03:36:17,255 --> 03:36:19,824
 TALKING ABOUT T CELLS.

4079
03:36:19,824 --> 03:36:21,526
 >> I NOTICED ON YOUR ID
THERE

4080
03:36:21,526 --> 03:36:27,465
 IS A PICTURE FROM MY LONG TIME

4081
03:36:27,465 --> 03:36:28,967
 COLLEAGUE LAKSHMI AND THAT

4082
03:36:28,967 --> 03:36:39,477
 WILL BE THE EXTENT THAT I

4083
03:36:40,378 --> 03:36:40,779
 SHOW.

4084
03:36:40,779 --> 03:36:45,317
 SO WE HAVE BEEN RUNNING THIS

4085
03:36:45,317 --> 03:36:55,860
 FOR YEARS AND TALKING ABOUT

4086
03:36:57,629 --> 03:37:01,299
 THE PERSPECTIVE, IS PHOSPORUS

4087
03:37:01,299 --> 03:37:07,739
 SERVE AS A BINDING FOR SH2

4088
03:37:07,739 --> 03:37:11,810
 PROTEINS AND MULTIPLE BREATHE

4089
03:37:11,810 --> 03:37:13,345
 TONES -- PROTEINS ARE THUS

4090
03:37:13,345 --> 03:37:15,080
 FORMED SO HERE YOU HAVE THE

4091
03:37:15,080 --> 03:37:17,482
 WORK AND WE'RE GOING TO FOCUS

4092
03:37:17,482 --> 03:37:19,818
 ON THIS COMPLEX BUT THERE ARE

4093
03:37:19,818 --> 03:37:20,719
 LITERALLY HUNDREDS OF THEM AND

4094
03:37:20,719 --> 03:37:26,291
 THIS IS HOW THE CRITICAL

4095
03:37:26,291 --> 03:37:29,794
 EVENTS OF TLC ACTIVATION IS

4096
03:37:29,794 --> 03:37:33,131
 INUSE ITD, IT IS RECRUITEDDED

4097
03:37:33,131 --> 03:37:41,373
 BUT DOESN'T COME ALONE TO THE

4098
03:37:41,373 --> 03:37:44,142
 LCG RECEPTOR SO THAT COMPLEX

4099
03:37:44,142 --> 03:37:50,181
 IS RESPONSIBLE FOR CALCIUM AND

4100
03:37:50,181 --> 03:37:53,351
 IB3 GENERATION AND BAD

4101
03:37:53,351 --> 03:37:55,387
 PRODUCTION, ACTIVATION OF GLS

4102
03:37:55,387 --> 03:37:57,722
 AND MANY EVENTS FOLLOW WHICH

4103
03:37:57,722 --> 03:37:59,190
 WE WON'T GO INTO BECAUSE WE

4104
03:37:59,190 --> 03:38:00,358
 KNOW THEM.

4105
03:38:00,358 --> 03:38:03,728
 SO BACK TO THIS COMPLEX, AS

4106
03:38:03,728 --> 03:38:07,465
 LONG AS WE HAVE BEEN DOING I

4107
03:38:07,465 --> 03:38:09,534
 AM IMAGING, 20, 25 YEARS AGO,

4108
03:38:09,534 --> 03:38:14,506
 WE START TO TAKE APART THIS

4109
03:38:14,506 --> 03:38:17,475
 COMPLEX AND SHOW THIS

4110
03:38:17,475 --> 03:38:19,110
 PRECIPITATION STUDY THAT IT

4111
03:38:19,110 --> 03:38:19,711
 EXISTED.

4112
03:38:19,711 --> 03:38:24,683
 SO WE STARTED BY PURIFYING IT

4113
03:38:24,683 --> 03:38:26,151
 AND MAKE PEPTIDES CONTAINING

4114
03:38:26,151 --> 03:38:28,620
 L.A. T AND ABLE TO SHOW ALL

4115
03:38:28,620 --> 03:38:29,688
 THESE INTERACTIONS OCCUR AT

4116
03:38:29,688 --> 03:38:31,790
 THAT LEVEL AND WE COULD

4117
03:38:31,790 --> 03:38:42,367
 MEASURE THE AFFIN TEASE USING

4118
03:38:44,202 --> 03:38:46,471
 ISOTHERMALCALOMETRY AND WILL

4119
03:38:46,471 --> 03:38:49,574
 SHOW THIS SH2 MEDIATOR ACTION

4120
03:38:49,574 --> 03:38:54,946
 HAS AN AFFINITY AS WELL AS

4121
03:38:54,946 --> 03:38:58,049
 THIS SH2 MEDIATOR AND THESE

4122
03:38:58,049 --> 03:39:01,920
 SH3 MEDIATORS ARE A LITTLE

4123
03:39:01,920 --> 03:39:09,160
 DIFFERENT, DOMAINS ACTING WITH

4124
03:39:09,160 --> 03:39:10,562
 EVERYBODY ENRICHED FOLINE

4125
03:39:10,562 --> 03:39:16,768
 CONVENIENCES AND THIS IS J THE

4126
03:39:16,768 --> 03:39:19,938
 JOHN HOPKINS CHART WHERE THEY

4127
03:39:19,938 --> 03:39:20,739
 GENERATED THE SEQUENCE IN THE

4128
03:39:20,739 --> 03:39:24,275
 LAB AND THIS IS USING A CELL

4129
03:39:24,275 --> 03:39:31,316
 LEAN RICH PEPTIDE WITH THE SH3

4130
03:39:31,316 --> 03:39:32,817
 PROTEIN OF GASSES, IT IS

4131
03:39:32,817 --> 03:39:38,490
 ACTUALLY THE HIGHEST AFFINITY 

4132
03:39:38,490 --> 03:39:40,625
 OF THESE INTERACTIONS AND THE

4133
03:39:40,625 --> 03:39:42,527
 SHOCK OF THIS IS THIS

4134
03:39:42,527 --> 03:39:45,430
 INTERACTION THAT HAD BEEN

4135
03:39:45,430 --> 03:39:46,898
 PREDICTED BY THE CORPORATE

4136
03:39:46,898 --> 03:39:49,901
 SOLICITATION IS THE 

4137
03:39:49,901 --> 03:39:59,144
 INTERACTION OF PLC, SH3 DOMAIN

4138
03:39:59,144 --> 03:40:03,148
 WITH ANOTHER POLICILY OR PLC

4139
03:40:03,148 --> 03:40:03,782
 DOMAIN.

4140
03:40:03,782 --> 03:40:05,417
 HOW CAN THAT BE?

4141
03:40:05,417 --> 03:40:07,385
 SO WE CAME BACK TO THIS IN THE

4142
03:40:07,385 --> 03:40:08,820
 LAB AND FIGURED THESE LITTLE

4143
03:40:08,820 --> 03:40:09,988
 REGIONS THEMSELVES ARE NOT THE

4144
03:40:09,988 --> 03:40:11,623
 WHOLE STORY AND YOU NEED THEM

4145
03:40:11,623 --> 03:40:15,193
 IN THE CONTEXT OF LARGER, PURE

4146
03:40:15,193 --> 03:40:17,395
 PROTEINS IF YOU WILL SO AGAIN

4147
03:40:17,395 --> 03:40:27,906
 WE'RE GOING TO WORK WITH A

4148
03:40:36,080 --> 03:40:36,648
 LITTLE DOUBLEYQUAT COMPLEX,

4149
03:40:36,648 --> 03:40:40,885
 YOU HAVE THE L.A. T CONSTRUCT,

4150
03:40:40,885 --> 03:40:45,023
 THE GADS CONSTRUCT AND PRETTY

4151
03:40:45,023 --> 03:40:48,493
 LARGE CHART OF SLP76 AND ON

4152
03:40:48,493 --> 03:40:50,728
 THREE OF THESE YOU WILL NOTICE

4153
03:40:50,728 --> 03:40:57,802
 THEY HAVE UNIQUE FLUORESCENT

4154
03:40:57,802 --> 03:40:59,003
 TAGS ATTACHED.

4155
03:40:59,003 --> 03:41:06,110
 SO THE 383 ON LAT AND SH3 ON

4156
03:41:06,110 --> 03:41:10,682
 GADS WITH 64 OF AND THERE WE

4157
03:41:10,682 --> 03:41:12,851
 COLLABORATED WITH PETER SHOOK

4158
03:41:12,851 --> 03:41:14,819
 WHO IS THIS BIOENGINEERING

4159
03:41:14,819 --> 03:41:16,354
 WIZARD HERE ON CAMPUS.

4160
03:41:16,354 --> 03:41:17,956
 SO WITH LIMITED TIME, I AM

4161
03:41:17,956 --> 03:41:19,691
 GOING TO TRY TO ZIP THROUGH A

4162
03:41:19,691 --> 03:41:21,860
 SLIDE HERE THAT IS SORT OF

4163
03:41:21,860 --> 03:41:22,727
 COMPLICATED AND THIS REQUIRES

4164
03:41:22,727 --> 03:41:33,238
 A LITTLE BALANCE, A LITTLE

4165
03:41:47,151 --> 03:41:47,719
 COORDINATION.

4166
03:41:47,719 --> 03:41:54,726
 SO YOU SEE THIS AFFINITY IS PL

4167
03:41:54,726 --> 03:42:00,064
 C1 AND THIS GRAPH REPRESENTS A

4168
03:42:00,064 --> 03:42:06,037
 RUNNING MIX WITH DIFFERENT

4169
03:42:06,037 --> 03:42:09,874
 SPECTOMETRY SO THE GADS AND

4170
03:42:09,874 --> 03:42:10,975
 SLP ARE ONE-ON-ONE AND THEN

4171
03:42:10,975 --> 03:42:13,678
 FOR SOME REASON, THE PLC AND

4172
03:42:13,678 --> 03:42:15,380
 FOR REASONS I WILL EXPLAIN IN

4173
03:42:15,380 --> 03:42:18,149
 A SECOND WE HAVE INCREASING

4174
03:42:18,149 --> 03:42:20,184
 CONCENTRATIONS OF PLC WITH A

4175
03:42:20,184 --> 03:42:22,086
 ONE TO ONE CONCENTRATION WITH

4176
03:42:22,086 --> 03:42:22,520
 THE OTHER.

4177
03:42:22,520 --> 03:42:24,556
 AND THE REASON FOR THAT IS IF

4178
03:42:24,556 --> 03:42:26,324
 YOU LOOK AT THE GREEN LINES,

4179
03:42:26,324 --> 03:42:28,526
 THAT IS ONE TO ONE TO ONE, ALL

4180
03:42:28,526 --> 03:42:30,595
 OF THEM AND YOU SEE THIS PEAK

4181
03:42:30,595 --> 03:42:32,463
 HERE AND THEN YOU SEE THIS

4182
03:42:32,463 --> 03:42:36,968
 PEAK HERE WHICH HAS TO BE THE

4183
03:42:36,968 --> 03:42:39,938
 TETRAMER, THE COMPLEX, BUT

4184
03:42:39,938 --> 03:42:40,972
 PRESUMABLY THE COMPLEX IS

4185
03:42:40,972 --> 03:42:43,274
 FALLING APART AND IT FALLS

4186
03:42:43,274 --> 03:42:45,743
 APART AS IT GOES THROUGH THE

4187
03:42:45,743 --> 03:42:47,178
 UNITED CURRENT AND AS IT

4188
03:42:47,178 --> 03:42:48,947
 LEAVES THE STATION, IT CAN'T

4189
03:42:48,947 --> 03:42:49,614
 GET BACK ON.

4190
03:42:49,614 --> 03:42:51,382
 SO YOU SEE THE SEPARATION

4191
03:42:51,382 --> 03:42:51,716
 THERE.

4192
03:42:51,716 --> 03:42:54,419
 SO WE FIGURE THERE IS A LOW

4193
03:42:54,419 --> 03:42:58,089
 AFFINITY FOR THE PLC, CAN WE

4194
03:42:58,089 --> 03:43:01,392
 JUST TITER THAT UP, RAISE THE

4195
03:43:01,392 --> 03:43:02,694
 RATIO OF PLC AND THAT IS WHAT

4196
03:43:02,694 --> 03:43:04,028
 YOU SEE HAPPENING HERE.

4197
03:43:04,028 --> 03:43:07,599
 SO AS IT TITERS UP, YOU HAVE

4198
03:43:07,599 --> 03:43:11,769
 THIS MOVEMENT HERE, SAME 

4199
03:43:11,769 --> 03:43:14,339
 MECHANISM, THE TETRAMER STAYS

4200
03:43:14,339 --> 03:43:16,007
 AROUND LONGER AND THE PLC

4201
03:43:16,007 --> 03:43:16,641
 FALLS OFF.

4202
03:43:16,641 --> 03:43:19,344
 SO THERE IS INCREASING PLC BUT

4203
03:43:19,344 --> 03:43:21,512
 AS YOU WILL NOTICE, IT IS

4204
03:43:21,512 --> 03:43:23,781
 CONSUMED AS WE GO TO THE BLUE

4205
03:43:23,781 --> 03:43:26,451
 AND THE RED.

4206
03:43:26,451 --> 03:43:28,653
 SO THIS MIGRATION REFLECTS

4207
03:43:28,653 --> 03:43:30,655
 THIS LOW AFFINITY INTERACTION

4208
03:43:30,655 --> 03:43:36,494
 OF PLC BUT THIS IS THE

4209
03:43:36,494 --> 03:43:37,195
 PREDICTED MOLECULAR WEIGHT OF

4210
03:43:37,195 --> 03:43:40,531
 THE MASS OF THE TETRAMER SO WE

4211
03:43:40,531 --> 03:43:44,402
 HAVE BEEN ABLE TO PROVE FOES

4212
03:43:44,402 --> 03:43:45,303
 FOUR MOLECULES COME TOGETHER

4213
03:43:45,303 --> 03:43:46,704
 AND WE CAN DEMONSTRATE THAT

4214
03:43:46,704 --> 03:43:47,071
 HERE.

4215
03:43:47,071 --> 03:43:49,440
 NOW IS THERE ANY CONSEQUENCE

4216
03:43:49,440 --> 03:43:51,409
 IN TERMS OF FUNCTION -- WELL

4217
03:43:51,409 --> 03:43:53,011
 HERE IS THE PICTURE AGAIN.

4218
03:43:53,011 --> 03:43:55,313
 WE HAVE THESE FOUR

4219
03:43:55,313 --> 03:43:58,383
 INTERACTIONS, FOUR INTERACTING

4220
03:43:58,383 --> 03:44:05,923
 SITES, SH2 WITH TYROSINE AND

4221
03:44:05,923 --> 03:44:07,425
 THEN CHOLINE ENRICHED HERE

4222
03:44:07,425 --> 03:44:10,495
 WITH THIS BEING THE WEAK LINK.

4223
03:44:10,495 --> 03:44:12,030
 DOES IT HAVE FUNCTIONAL

4224
03:44:12,030 --> 03:44:12,363
 IMPACT?

4225
03:44:12,363 --> 03:44:14,565
 STILL WORKING WITH FOLATE

4226
03:44:14,565 --> 03:44:19,170
 PROTEINS TURNING TO THE WORK

4227
03:44:19,170 --> 03:44:21,205
 OF JUNE WADDI ITSTILL IN THE

4228
03:44:21,205 --> 03:44:28,246
 LAB AND THE SL LP AND A LARGE

4229
03:44:28,246 --> 03:44:37,488
 CHUNK OF SLP AND FULL LENGTH 

4230
03:44:37,488 --> 03:44:44,262
 GADS AND WHAT WE WANTED TO SEE

4231
03:44:44,262 --> 03:44:51,035
 IS IF THIS COULD BE LINKED TO

4232
03:44:51,035 --> 03:44:55,406
 THE MOLECULES.

4233
03:44:55,406 --> 03:45:02,413
 SO WE ATTACH UNILAMELLAR

4234
03:45:02,413 --> 03:45:07,618
 VESICLES, WE HAVE PROLINE AND

4235
03:45:07,618 --> 03:45:10,321
 THAT ALLOWS IT TO DOCK ON TO

4236
03:45:10,321 --> 03:45:11,255
 THE MEMBRANES AND THEN WE WILL

4237
03:45:11,255 --> 03:45:13,357
 SEE IF THESE OTHER GUYS CAN

4238
03:45:13,357 --> 03:45:15,593
 FORM A COMPLEX AND WHAT

4239
03:45:15,593 --> 03:45:16,294
 HAPPENS THEN.

4240
03:45:16,294 --> 03:45:19,097
 SO NEED TO TELL YOU TWO OTHER

4241
03:45:19,097 --> 03:45:20,298
 THINGS.

4242
03:45:20,298 --> 03:45:21,566
 THOSE IN THE AUDIENCE OF MY

4243
03:45:21,566 --> 03:45:23,000
 AGE WILL REMEMBER THAT YOU

4244
03:45:23,000 --> 03:45:33,444
 USED TO BE ABLE TO BUY

4245
03:45:35,847 --> 03:45:37,548
 TRITIALE-- TRITIATED LIPIDS IN

4246
03:45:37,548 --> 03:45:38,516
 CHEMICAL CONCENTRATIONS BUT

4247
03:45:38,516 --> 03:45:40,752
 THE COMPANIES DON'T MAKE THEM

4248
03:45:40,752 --> 03:45:51,162
 ANYMORE SO THERE IS THIS

4249
03:45:51,162 --> 03:45:53,264
 COMPOUND WHERE YOU GENERATE A

4250
03:45:53,264 --> 03:45:54,699
 VERY RED FLUORESCENT WHICH YOU

4251
03:45:54,699 --> 03:45:55,399
 CAN MEASURE.

4252
03:45:55,399 --> 03:45:57,769
 IN THE PRESENCE OF IP3 WHICH

4253
03:45:57,769 --> 03:46:04,642
 IS THE PRODUCT WE'RE GOING TO 

4254
03:46:04,642 --> 03:46:07,178
 BE MEASURING, THE IT IS BOUND

4255
03:46:07,178 --> 03:46:09,647
 TO THE ITRIUM AND NOW YOU LOSE

4256
03:46:09,647 --> 03:46:12,550
 THE RED SIGNAL SO YOU SEE A

4257
03:46:12,550 --> 03:46:14,352
 NEGATIVE PEAK.

4258
03:46:14,352 --> 03:46:16,754
 THIS IS THE ABSORB BENZ OF THE

4259
03:46:16,754 --> 03:46:27,331
 RED AND IT MEASURES A NEGATIVE

4260
03:46:27,832 --> 03:46:28,699
 IP3.

4261
03:46:28,699 --> 03:46:30,168
 HERE IS AN INITIAL EXPERIMENT,

4262
03:46:30,168 --> 03:46:33,204
 I NEED TO ADD ONE ONE POINT --

4263
03:46:33,204 --> 03:46:34,272
 WELL, NOT YET.

4264
03:46:34,272 --> 03:46:44,849
 WE HAVE THE LAST WHICH IS FOSS

4265
03:46:49,754 --> 03:46:52,590
 NORTHERN-- PHOSPHO LAT WILL

4266
03:46:52,590 --> 03:46:59,564
 BIND PLC IN THIS EXPERIMENT 

4267
03:46:59,564 --> 03:47:04,936
 BUT NOT THE NONPHOSPHO LAT AND

4268
03:47:04,936 --> 03:47:11,309
 IF IT BINDS YOU CAN MEASURE A

4269
03:47:11,309 --> 03:47:13,611
 CLEAVE VANS SO THAT IS

4270
03:47:13,611 --> 03:47:17,315
 BRINGING PLC TO THE MEMBRANE

4271
03:47:17,315 --> 03:47:17,849
 ARTIFICIALLY.

4272
03:47:17,849 --> 03:47:22,587
 I NEED TO TELL YOU THAT YOU

4273
03:47:22,587 --> 03:47:28,693
 NEED PLC TO PHOSPHORYLATE IT

4274
03:47:28,693 --> 03:47:39,270
 AND IN OUR LAB WE WILL INTRIPS

4275
03:47:41,472 --> 03:47:42,840
 INTRINSICALLY PHOSPHORYLATE IT

4276
03:47:42,840 --> 03:47:48,412
 AND WITH THAT, WE NEED TO DO

4277
03:47:48,412 --> 03:47:49,847
 THE BIG EXPERIMENT.

4278
03:47:49,847 --> 03:47:51,849
 OOPS, GIVING AWAY THE PUNCH

4279
03:47:51,849 --> 03:47:52,483
 LINE.

4280
03:47:52,483 --> 03:47:56,153
 SO ON THE LEFT HERE, NOW WE

4281
03:47:56,153 --> 03:47:59,457
 CAN JUST ADD PLC BY ITSELF AND

4282
03:47:59,457 --> 03:48:01,592
 YOU GET A LITTLE BACKGROUND

4283
03:48:01,592 --> 03:48:11,836
 ACTIVITY BUT IF YOU ADD IT TO

4284
03:48:11,836 --> 03:48:13,337
 THE PHOSPHORYLATED LAT, YOU

4285
03:48:13,337 --> 03:48:18,509
 GET A LOT OF BINDING AND YOU

4286
03:48:18,509 --> 03:48:25,216
 CAN ADD IT TO THE GAD.

4287
03:48:25,216 --> 03:48:27,485
 SO YOU GET A LITTLE ACTIVITY,

4288
03:48:27,485 --> 03:48:28,819
 BOUNCING OFF THE MEMBRANES AND

4289
03:48:28,819 --> 03:48:32,723
 THERE IS MORE ACTIVITY IN THE

4290
03:48:32,723 --> 03:48:33,891
 FOSS FOR LATE FIELD.

4291
03:48:33,891 --> 03:48:36,294
 SO HERE IS WHAT WE HAVE SHOWN

4292
03:48:36,294 --> 03:48:38,195
 YOU BEFORE, ATTACH PLC TO THE

4293
03:48:38,195 --> 03:48:41,365
 LAT AND DO BETTER AND THIS IS

4294
03:48:41,365 --> 03:48:43,868
 THE INTERESTING RESULT.

4295
03:48:43,868 --> 03:48:49,140
 THE ADDITION OF GAD AND L.A. T

4296
03:48:49,140 --> 03:48:50,541
 GIVES YOU MORE OBJECTIVITY.

4297
03:48:50,541 --> 03:48:52,376
 SO HOW DOES THIS WORK?

4298
03:48:52,376 --> 03:49:01,018
 THIS IS FROM THE LAB AT PLC

4299
03:49:01,018 --> 03:49:11,462
 WHICH IS AN ACTIVE ENZYME WITH

4300
03:49:11,462 --> 03:49:12,763
 PHOSPHORYLATE AND THEY COVER

4301
03:49:12,763 --> 03:49:17,435
 UP THE ACTIVE SITE WHICH IS

4302
03:49:17,435 --> 03:49:19,437
 BLOCKED AND PHOSPHORYLATION OF

4303
03:49:19,437 --> 03:49:20,371
 PLC WOULD BE OCCURRING HERE

4304
03:49:20,371 --> 03:49:23,607
 AND THAT HAS BEEN SHOWN TO

4305
03:49:23,607 --> 03:49:25,142
 INDUCE AN OPENING OF THIS

4306
03:49:25,142 --> 03:49:29,947
 COMPLEX AND MAKE IT MORE

4307
03:49:29,947 --> 03:49:31,248
 ACCESSIBLE TO THE SUBSTRATE

4308
03:49:31,248 --> 03:49:33,384
 AND WE WOULD PROPOSE THE

4309
03:49:33,384 --> 03:49:35,619
 FORMATION OF THE BINDING OF

4310
03:49:35,619 --> 03:49:38,956
 THE SH2 AND SH3'S IN THIS

4311
03:49:38,956 --> 03:49:41,258
 COMPLEX WILL KICK IT OUT

4312
03:49:41,258 --> 03:49:44,362
 FURTHER AND INCREASE THE

4313
03:49:44,362 --> 03:49:48,032
 ACTIVATION STILL FURTHER.

4314
03:49:48,032 --> 03:49:52,103
 OKAY, SO SOME OF THE MAPPING

4315
03:49:52,103 --> 03:49:55,072
 OF THESE -- HERE AGAIN IS THIS

4316
03:49:55,072 --> 03:49:57,708
 IDEA THAT WE HAVE THIS

4317
03:49:57,708 --> 03:50:01,212
 INTERACTION HERE WHICH IS VERY

4318
03:50:01,212 --> 03:50:01,779
 WEAK.

4319
03:50:01,779 --> 03:50:06,283
 WE CAN DEMONSTRATE IT IN THE

4320
03:50:06,283 --> 03:50:07,251
 FORMATION OF TETRAMER BUT IT

4321
03:50:07,251 --> 03:50:09,186
 WILL HAVE AN OPEN AND CLOSED

4322
03:50:09,186 --> 03:50:10,888
 REACTION AS WELL AND PERHAPS

4323
03:50:10,888 --> 03:50:14,558
 WHEN THAT HAPPENS, THE WHOLE

4324
03:50:14,558 --> 03:50:15,359
 COMPLEX FALLS APART.

4325
03:50:15,359 --> 03:50:18,195
 SO LONG AGO IN THE EARLY DAYS

4326
03:50:18,195 --> 03:50:19,597
 OF SH3 STUDIES WHEN PEOPLE

4327
03:50:19,597 --> 03:50:23,667
 DON'T KNOW WHAT SA3 DID, THIS

4328
03:50:23,667 --> 03:50:25,102
 GROUP DID A FACE DISPLAY

4329
03:50:25,102 --> 03:50:30,307
 ANALYSIS TO FIND THE OPTIMAL

4330
03:50:30,307 --> 03:50:32,710
 SH3 CONSENSUS -- BINDING SITE

4331
03:50:32,710 --> 03:50:33,544
 CONSENSUS SEQUENCE AND THAT IS

4332
03:50:33,544 --> 03:50:35,880
 WHAT IS SHOWN HERE IN THE

4333
03:50:35,880 --> 03:50:36,280
 MIDDLE LINE.

4334
03:50:36,280 --> 03:50:39,083
 HERE IS THE PAROLE LEAN RICH

4335
03:50:39,083 --> 03:50:45,823
 REGION WHICH WE PRESUME IS

4336
03:50:45,823 --> 03:50:48,826
 ACTING WITH THE SL & HERE
IS A

4337
03:50:48,826 --> 03:50:52,463
 BETTER BINDING DOMAIN AND ONE 

4338
03:50:52,463 --> 03:50:57,802
 CAN ACTUALLY KILL THESE CYTES

4339
03:50:57,802 --> 03:50:58,602
 WHICH HE DID.

4340
03:50:58,602 --> 03:51:02,306
 IT IS NOT AN ALL OR NONE

4341
03:51:02,306 --> 03:51:07,978
 ALTHOUGH WHEN YOU LOOK AT THIS

4342
03:51:07,978 --> 03:51:11,982
 DEAD ONE, YOU CAN SEE THE

4343
03:51:11,982 --> 03:51:13,684
 DIFFERENCE, IT IS ABOUT

4344
03:51:13,684 --> 03:51:17,054
 20 PERCENT BETTER SO WHAT ARE

4345
03:51:17,054 --> 03:51:18,622
 THE CONSEQUENCES THERE WHEN

4346
03:51:18,622 --> 03:51:20,624
 THEY ADDED AND MADE THE

4347
03:51:20,624 --> 03:51:24,795
 COMPLEX OF PROTEINS COMPARING

4348
03:51:24,795 --> 03:51:27,198
 THE WILD CYTE AND THE ACTIVE

4349
03:51:27,198 --> 03:51:28,766
 CYTE AND THIS IS WHAT I HAVE

4350
03:51:28,766 --> 03:51:32,403
 JUST SHOWN YOU, A LITTLE PLC

4351
03:51:32,403 --> 03:51:34,839
 ALONE GIVES YOU REACTIVITY,

4352
03:51:34,839 --> 03:51:39,410
 BRING IT TO THE L.A. T, IT

4353
03:51:39,410 --> 03:51:44,381
 GETS BETTER AND THE GADS,

4354
03:51:44,381 --> 03:51:45,649
 BECOMES ACTIVE STILL.

4355
03:51:45,649 --> 03:51:49,787
 WHEN YOU ADD THE SEQUENCE, YOU

4356
03:51:49,787 --> 03:51:50,254
 DO BETTER STILL.

4357
03:51:50,254 --> 03:51:56,727
 THE FACT YOU SEE SOMETHING

4358
03:51:56,727 --> 03:51:57,761
 WITH THE DEAD THING IN, YOU

4359
03:51:57,761 --> 03:52:01,599
 HAVE TO THINK OF ALL THESE

4360
03:52:01,599 --> 03:52:03,067
 CYTES OF OPENING AND CLOSING,

4361
03:52:03,067 --> 03:52:05,436
 THAT IS HOW THE BINDING WORKS

4362
03:52:05,436 --> 03:52:09,740
 BUT IN A SITUATION WHERE YOU 

4363
03:52:09,740 --> 03:52:13,811
 HAVE THE ACTIVE BINDING WHERE

4364
03:52:13,811 --> 03:52:15,980
 THE TETRAMER IS MORE STABLE,

4365
03:52:15,980 --> 03:52:17,381
 THE REST OF THE COMPLEX IS

4366
03:52:17,381 --> 03:52:19,917
 FORMED AND YOU WILL GET A

4367
03:52:19,917 --> 03:52:20,384
 LITTLE ACTIVITY.

4368
03:52:20,384 --> 03:52:23,354
 NOW WE'RE GOING TO SWITCH TO

4369
03:52:23,354 --> 03:52:25,156
 OLD FASHIONED DEVELOPMENT AND

4370
03:52:25,156 --> 03:52:35,432
 IMMUNOLOGY. 

4371
03:53:00,124 --> 03:53:01,525
 DOES THIS MUTATION SO NOW WE

4372
03:53:01,525 --> 03:53:06,130
 HAVE THE T CELL SPECIFIC

4373
03:53:06,130 --> 03:53:11,202
 CONDITIONAL SLP76 AND PUT IN 

4374
03:53:11,202 --> 03:53:14,738
 THE KI MUTATION AND ROSA YFP

4375
03:53:14,738 --> 03:53:23,113
 SO THE BOTTOM LINE, YOU

4376
03:53:23,113 --> 03:53:24,348
 INTRODUCE THIS CONSTRUCT, YOU

4377
03:53:24,348 --> 03:53:26,383
 KNOCK THIS SOUTH AND ARE LEFT

4378
03:53:26,383 --> 03:53:28,953
 WITH JUST THE MUTATED HIGH

4379
03:53:28,953 --> 03:53:31,522
 AFFINITY SITE AND YOU WILL

4380
03:53:31,522 --> 03:53:35,893
 ALSO HAVE RED CELLS.

4381
03:53:35,893 --> 03:53:36,293
 GREEN CELLS.

4382
03:53:36,293 --> 03:53:38,229
 THERE YOU GO.

4383
03:53:38,229 --> 03:53:39,196
 SO THAT'S WHAT HAPPENED.

4384
03:53:39,196 --> 03:53:40,698
 AND HERE IS SOME OF THE --

4385
03:53:40,698 --> 03:53:42,099
 JUST GOING TO SHOW A LITTLE

4386
03:53:42,099 --> 03:53:45,436
 BIT OF THE STUDY SO YOU HAVE

4387
03:53:45,436 --> 03:53:47,504
 THESE VERY COMPLEX GENOTYPES

4388
03:53:47,504 --> 03:53:49,273
 AND MARKER ANALYSIS BUT THE

4389
03:53:49,273 --> 03:53:51,308
 BOTTOM LINE IS HERE IS THE

4390
03:53:51,308 --> 03:53:55,446
 WILD TYPE MOUSE AND HERE IS

4391
03:53:55,446 --> 03:53:58,482
 THE SLP TYPE MOUSE AND YOU

4392
03:53:58,482 --> 03:54:00,417
 TAKE THE T CELLS FROM THAT AND

4393
03:54:00,417 --> 03:54:02,653
 THEY ARE RECEPTOR POSITIVES IN

4394
03:54:02,653 --> 03:54:05,789
 BOTH CASES, YOU MIX THESE ON

4395
03:54:05,789 --> 03:54:08,192
 TO PEPTIDE LOADED DEPLETED T

4396
03:54:08,192 --> 03:54:09,560
 CELLS AND STIMULATE WITH WHAT

4397
03:54:09,560 --> 03:54:11,929
 YOU ALREADY HEARD ABOUT IN

4398
03:54:11,929 --> 03:54:15,532
 EARLIER TALKS, THE LT1 SERIES,

4399
03:54:15,532 --> 03:54:19,503
 THESE WOULD BE THE WILD TYPE

4400
03:54:19,503 --> 03:54:20,804
 WITH DECREASING AFFIN TEASE

4401
03:54:20,804 --> 03:54:22,239
 AND GIVING TO INCREASING

4402
03:54:22,239 --> 03:54:23,374
 RESPONSE AND HERE ARE THE

4403
03:54:23,374 --> 03:54:23,741
 RESULT.

4404
03:54:23,741 --> 03:54:24,808
 YOU CAN'T SEE A DIFFERENCE

4405
03:54:24,808 --> 03:54:27,144
 WHEN YOU USE THE WILD TYPE ODA

4406
03:54:27,144 --> 03:54:34,184
 BUT AS YOU SORT FTITER DOWN 

4407
03:54:34,184 --> 03:54:39,990
 YOUR AFFINITY PEPTIDES, Q T4

4408
03:54:39,990 --> 03:54:44,094
 AND Q4H7 YOU SEE THOSE HAVE A

4409
03:54:44,094 --> 03:54:47,231
 SLIGHTLY BETTER RESPONSE TO

4410
03:54:47,231 --> 03:54:49,366
 THE TITER AND EVEN IF YOU GET

4411
03:54:49,366 --> 03:54:50,534
 THE SATURATION, YOU ARE

4412
03:54:50,534 --> 03:54:52,536
 GETTING THIS SHIFT SO YOU ARE

4413
03:54:52,536 --> 03:54:54,138
 GETTING THIS ENHANCED RESPONSE

4414
03:54:54,138 --> 03:54:56,340
 BY INCREASING THE AFFINITY OF

4415
03:54:56,340 --> 03:54:59,643
 THAT PEPTIDE AND PRESUMABLY

4416
03:54:59,643 --> 03:55:02,179
 THE KINETICS OF THE DURATION

4417
03:55:02,179 --> 03:55:07,351
 OF THAT PERSISTENCE OF THE AT

4418
03:55:07,351 --> 03:55:17,795
 THE TIME -- TETRAMER. 

4419
03:56:11,115 --> 03:56:14,518
 SOMEBODY PAUSE IN --

4420
03:56:14,518 --> 03:56:24,995
 [ PAUSE IN CAPTIONING ] 

4421
03:59:21,473 --> 03:59:22,107
>> OKAY, LET'S EVERYONE,
PLEASE

4422
03:59:22,107 --> 03:59:22,974
TAKE YOUR SEATS.

4423
03:59:22,974 --> 03:59:24,976
WE'RE GOING TO GET STARTED WITH

4424
03:59:24,976 --> 03:59:29,981
THIS AFTERNOON'S SESSION.

4425
03:59:29,981 --> 03:59:31,049
SO WE STAY ON TIME.

4426
03:59:31,049 --> 03:59:33,351
I THINK WE ONLY HAVE THE ROOM UL

4427
03:59:33,351 --> 03:59:33,952
5:00.

4428
03:59:33,952 --> 03:59:44,663
SO, WE DON'T WANT TO GET THROWN 

4429
03:59:56,208 --> 03:59:56,775
OUT.

4430
03:59:56,775 --> 04:00:03,348
WE HAVE TO WAIT FOR AL TO SIT D.

4431
04:00:03,348 --> 04:00:05,083
OKAY, SO WELCOME TO SESSION 6,

4432
04:00:05,083 --> 04:00:07,452
WE'RE GOING TO TALK ABOUT IMMUNE

4433
04:00:07,452 --> 04:00:11,890
CELL FUNCTION AND OUR FIRST SPER

4434
04:00:11,890 --> 04:00:13,258
IS PAMELA SCHWARTZBERG -- I THIK

4435
04:00:13,258 --> 04:00:15,794
MAYBE SOME PEOPLE KNOW YOU?

4436
04:00:15,794 --> 04:00:16,361
[ LAUGHS ]

4437
04:00:16,361 --> 04:00:18,497
IF THERE IS ANYONE IN HERE WHO

4438
04:00:18,497 --> 04:00:19,764
DOESN'T KNOW PAM, THEY NEED TO

4439
04:00:19,764 --> 04:00:20,665
LEAVE RIGHT NOW.

4440
04:00:20,665 --> 04:00:22,801
AND PAM IS GOING TO TELL US ABOT

4441
04:00:22,801 --> 04:00:27,405
HER WORK ON PI3 KINASE AND

4442
04:00:27,405 --> 04:00:28,907
AMBULANCING T-CELL ACTIVATION AD

4443
04:00:28,907 --> 04:00:29,207
EXHAUSTION.

4444
04:00:29,207 --> 04:00:29,741
>> THANK YOU VERY MUCH.

4445
04:00:29,741 --> 04:00:32,143
AND I WANT TO THANK THE ORGANIZS

4446
04:00:32,143 --> 04:00:33,478
FOR AN INCREDIBLE MEETING.

4447
04:00:33,478 --> 04:00:35,881
IT'S A MEETING WHERE YOU JUST FL

4448
04:00:35,881 --> 04:00:38,183
GREAT ABOUT BEING AT NIH, WHICH

4449
04:00:38,183 --> 04:00:39,784
PROBABLY OVER THE WEEKEND, WE WT

4450
04:00:39,784 --> 04:00:43,989
FEEL SO GREAT ABOUT, BUT THAT'S

4451
04:00:43,989 --> 04:00:44,289
OKAY.

4452
04:00:44,289 --> 04:00:46,091
TODAY I THOUGHT I'D TELL YOU A

4453
04:00:46,091 --> 04:00:52,063
SHORT STORY ABOUT PI3 KINASE ONS

4454
04:00:52,063 --> 04:00:54,599
EFFECT ON EXHAUSTION.

4455
04:00:54,599 --> 04:00:55,734
SO, T-CELL EXHAUSTION, WHICH

4456
04:00:55,734 --> 04:00:57,202
SURPRISED ME WE HAVEN'T DISCUSSE

4457
04:00:57,202 --> 04:01:02,307
YET, IS AN ADAPTIVE STATE OF

4458
04:01:02,307 --> 04:01:04,109
HYPERRESPONSIVENESS TO -- WHICH

4459
04:01:04,109 --> 04:01:07,579
RESULTS IN RESPONSE TO CHRONIC R

4460
04:01:07,579 --> 04:01:08,647
PERSISTENT ANTIGEN STIMULATION.

4461
04:01:08,647 --> 04:01:10,382
WE TEND TO THINK ABOUT THIS IN

4462
04:01:10,382 --> 04:01:15,387
TERMS OF LOSS OF CONTROL AGAINST

4463
04:01:15,387 --> 04:01:16,788
VIRUSES AND TUMORS.

4464
04:01:16,788 --> 04:01:18,790
IT'S IMPORTANT TO REALIZE THAT

4465
04:01:18,790 --> 04:01:21,092
EXHAUSTION IS AN ADAPTIVE PHENOE

4466
04:01:21,092 --> 04:01:24,996
AND HELPS PREVENT IMMUNOPATHOLOY

4467
04:01:24,996 --> 04:01:26,698
UNDER CONDITIONS OF CONTINUAL

4468
04:01:26,698 --> 04:01:26,998
STIMULATION.

4469
04:01:26,998 --> 04:01:28,400
AND SO AS WE ASK THE QUESTION OF

4470
04:01:28,400 --> 04:01:33,672
HOW CAN WE REINVIGORATE EFFECTOR

4471
04:01:33,672 --> 04:01:34,673
T-CELL FUNCTION UNDER CONDITIONF

4472
04:01:34,673 --> 04:01:36,908
EXHAUSTION, WE HAVE TO KEEP THOE

4473
04:01:36,908 --> 04:01:38,910
ISSUES OF BALANCE IN MIND.

4474
04:01:38,910 --> 04:01:41,112
AND SO WE GOT INTO THIS THROUGHR

4475
04:01:41,112 --> 04:01:43,815
STUDIES OF A PRIMARY

4476
04:01:43,815 --> 04:01:45,717
IMMUNODEFICIENCY ACTIVATED PI3

4477
04:01:45,717 --> 04:01:47,018
KINASE DELTA SYNDROME.

4478
04:01:47,018 --> 04:01:50,855
THIS IS AN IMMUNODEFICIENCY

4479
04:01:50,855 --> 04:01:52,023
CHARACTERED RIGHTS BY CMD,

4480
04:01:52,023 --> 04:01:53,592
RECURRENT RESPIRATORY AND GUT

4481
04:01:53,592 --> 04:01:55,527
INFECTIONS AND ALSO IMMUNE DIGS

4482
04:01:55,527 --> 04:01:55,894
REGULATION.

4483
04:01:55,894 --> 04:02:01,433
SO THE PATIENTS HAVE LYMPHOPENIA

4484
04:02:01,433 --> 04:02:06,705
YET AND ALTERED T AND C CELL

4485
04:02:06,705 --> 04:02:10,475
POPULATIONS AND A FEATURE OF THE

4486
04:02:10,475 --> 04:02:12,911
MUCOSAL LYMPHOID NODULES.

4487
04:02:12,911 --> 04:02:15,380
SEQUENCING OF THE GENOMES OF THE

4488
04:02:15,380 --> 04:02:17,749
EXOMES OF THESE PATIENTS REVEALD

4489
04:02:17,749 --> 04:02:19,417
THAT THEY HARBORED HETEROZYGOTE

4490
04:02:19,417 --> 04:02:24,322
ACTIVATING MUTATIONS AFFECTING 0

4491
04:02:24,322 --> 04:02:27,926
DELTA, THE SUBUNIT OF A

4492
04:02:27,926 --> 04:02:30,428
HEMATOPOIETIC SPECIFIC CLASS 1A3

4493
04:02:30,428 --> 04:02:31,429
KINASE DELTA.

4494
04:02:31,429 --> 04:02:35,934
AND SO PI3 KINASE IS THE CLASS ,

4495
04:02:35,934 --> 04:02:40,205
ACTIVATED DOWNSTREAM OF MANY

4496
04:02:40,205 --> 04:02:40,472
SIGNALING.

4497
04:02:40,472 --> 04:02:44,175
THEY WILL PHOSPHORYLATE TO GENEE

4498
04:02:44,175 --> 04:02:47,846
PIP 3 AND THAT WILL CREATE --

4499
04:02:47,846 --> 04:02:50,515
RESULT IN THE RECRUITMENT OF

4500
04:02:50,515 --> 04:02:53,818
PROTEINS THAT HAVE HOMOLOGY OR

4501
04:02:53,818 --> 04:02:55,854
OTHER PIP 3 BINDING DOMAINS WHEE

4502
04:02:55,854 --> 04:02:56,955
THEY GET ACTIVATED.

4503
04:02:56,955 --> 04:02:59,758
AND THE BEST KNOWN ARE THE AKT

4504
04:02:59,758 --> 04:03:00,358
KINASES.

4505
04:03:00,358 --> 04:03:03,862
AKT WILL PHOSPHORYLATE A RANGE F

4506
04:03:03,862 --> 04:03:05,563
DOWNSTREAM EFFECTORS LEADING TO

4507
04:03:05,563 --> 04:03:12,370
ACTIVATION OF mTOR REGULATION OF

4508
04:03:12,370 --> 04:03:14,305
PROTEINS INVOLVED IN CELL SURVIL

4509
04:03:14,305 --> 04:03:16,074
AS WELL AS PHOSPHORYLATION OF

4510
04:03:16,074 --> 04:03:19,477
TRANSCRIPTION FACTORS SUCH AS TE

4511
04:03:19,477 --> 04:03:21,279
FOXO FACTORS AND PHOSPHORYLATIOF

4512
04:03:21,279 --> 04:03:23,782
THEM LEADS TO SEQUESTRATION OUTE

4513
04:03:23,782 --> 04:03:25,950
OF THE NUCLEUS AND IN ACTIVATIO.

4514
04:03:25,950 --> 04:03:28,853
SO TOGETHER, THOSE EFFECTS CONSE

4515
04:03:28,853 --> 04:03:31,956
TO REGULATE METABOLISM, GROWTH,

4516
04:03:31,956 --> 04:03:33,958
PROLIFERATION, SURVIVAL, MIGRATN

4517
04:03:33,958 --> 04:03:35,994
AND DIFFERENTIATION WHICH WILL E

4518
04:03:35,994 --> 04:03:36,528
KEY FOR T-CELL FUNCTION.

4519
04:03:36,528 --> 04:03:39,264
THE QUESTION WE HAD IS WHY DO TE

4520
04:03:39,264 --> 04:03:42,467
PATIENTS WITH ACTIVATED PI3 KINE

4521
04:03:42,467 --> 04:03:44,569
SYNDROME, WHY DON'T THEY CLEAR

4522
04:03:44,569 --> 04:03:45,770
CERTAIN VIRAL INFECTIONS?

4523
04:03:45,770 --> 04:03:47,772
TOW TRY TO ADDRESS THESE QUESTIS

4524
04:03:47,772 --> 04:03:49,974
WE GENERATED MICE OR KNOCKED INE

4525
04:03:49,974 --> 04:03:51,876
MOST COMMON MUTATION ACTIVATING

4526
04:03:51,876 --> 04:03:54,779
MUTATION INTO PI3 KINASE DELTA D

4527
04:03:54,779 --> 04:03:57,148
THEY RECAPITULATED MANY FEATUREF

4528
04:03:57,148 --> 04:03:58,483
THE PATIENTS.

4529
04:03:58,483 --> 04:04:00,485
SO THEY WERE LYMPHOPENIC IN THE

4530
04:04:00,485 --> 04:04:01,219
BLOOD.

4531
04:04:01,219 --> 04:04:03,655
THEY HAD LIMP KNOP THEE AND

4532
04:04:03,655 --> 04:04:05,690
INCREASED ACTIVATED T-CELLS AND

4533
04:04:05,690 --> 04:04:08,727
THEY ALSO GOT THOSE MUCOSAL

4534
04:04:08,727 --> 04:04:08,993
FOLLICLE.

4535
04:04:08,993 --> 04:04:19,604
THEY NICELY MODELED THE PATIENTF

4536
04:04:22,273 --> 04:04:25,877
WE STIMULATED THEM WITH ANTI-CD3

4537
04:04:25,877 --> 04:04:28,446
AND CD TREAT, WHAT WE SAW IS THT

4538
04:04:28,446 --> 04:04:30,715
THESE CELLS UNDERWENT MASSIVE

4539
04:04:30,715 --> 04:04:31,616
APOPTOSIS.

4540
04:04:31,616 --> 04:04:33,985
AND WE LINKED THIS TO INCREASEDD

4541
04:04:33,985 --> 04:04:36,888
HIGH LEVELS OF EXPRESSION OF FAS

4542
04:04:36,888 --> 04:04:39,691
LIGAND STIMULATING THESE CELLS O

4543
04:04:39,691 --> 04:04:42,494
UNDERGO APOPTOSIS THROUGH FAST

4544
04:04:42,494 --> 04:04:43,194
MEDIATED PATHWAYS.

4545
04:04:43,194 --> 04:04:45,196
WHEN WE LOOKED AT THE SURVIVING

4546
04:04:45,196 --> 04:04:47,298
CELLS, WE REALIZED THAT THESE CS

4547
04:04:47,298 --> 04:04:49,601
HAD AN ACCELERATED EFFECTOR CELL

4548
04:04:49,601 --> 04:04:53,171
PROGRAM AND SO THEY PRODUCED EAY

4549
04:04:53,171 --> 04:04:58,510
AND INCREASED INTERFERON GAMMA, 

4550
04:04:58,510 --> 04:05:02,781
TNF -- AND ELEVATED mTOR ONE AND

4551
04:05:02,781 --> 04:05:05,183
MYC AND DRIVEN SIGNATURES ALONG

4552
04:05:05,183 --> 04:05:07,719
WITH ALTERED TRANSCRIPTION AND

4553
04:05:07,719 --> 04:05:08,920
EPIGENETIC LANDSCAPES.

4554
04:05:08,920 --> 04:05:11,089
WHAT THESE CELLS LOOKED LIKE IS

4555
04:05:11,089 --> 04:05:15,426
THAT THEY HAD A PUSH FROM A NAIE

4556
04:05:15,426 --> 04:05:16,694
PHENOTYPE TO A TERMINAL EFFECTOR

4557
04:05:16,694 --> 04:05:18,930
PROGRAM AND THIS IS AT THE EXPEE

4558
04:05:18,930 --> 04:05:20,532
OF THE FORMATION OF CENTRAL MEM.

4559
04:05:20,532 --> 04:05:25,103
AND WE CAN SEE THAT HERE IF YOU

4560
04:05:25,103 --> 04:05:27,005
LOOK IN FLOW PLOT POST INFECTIO,

4561
04:05:27,005 --> 04:05:29,507
THIS IS TWO WEEKS POST INFECTION

4562
04:05:29,507 --> 04:05:34,179
WITH ACUTE LCMV, WE CAN SEE THAT

4563
04:05:34,179 --> 04:05:36,581
WILDTYPE CELLS A GRAND ZYME P HH

4564
04:05:36,581 --> 04:05:38,616
POPULATION REPRESENTING THE

4565
04:05:38,616 --> 04:05:41,519
EFFECTOR CELLS AS WELL AS THIS 1

4566
04:05:41,519 --> 04:05:43,121
HIGH POPULATION THAT REPRESENTSE

4567
04:05:43,121 --> 04:05:44,856
PRECURSORS TO CENTRAL MEMORY.

4568
04:05:44,856 --> 04:05:48,126
IN THE PI3 KINASE MUTANT CELLS,U

4569
04:05:48,126 --> 04:05:50,428
CAN SEE A LARGE AMOUNT OF THESE

4570
04:05:50,428 --> 04:05:52,430
EFFECTOR CELLS BUT YOU LOSE

4571
04:05:52,430 --> 04:05:54,999
EXPRESSION OF THE TCF ONE POSITE

4572
04:05:54,999 --> 04:05:55,300
POPULATION.

4573
04:05:55,300 --> 04:05:58,937
AND THIS IS REALLY OF INTEREST O

4574
04:05:58,937 --> 04:06:01,506
US BECAUSE CHUAN WU HAD DONE INR

4575
04:06:01,506 --> 04:06:03,341
LAB, ALONG WITH SEVERAL OTHER L,

4576
04:06:03,341 --> 04:06:05,610
A NUMBER OF YEARS AGO, THAT SHON

4577
04:06:05,610 --> 04:06:09,314
THAT TCF7, WHICH ENCODES TCF1,

4578
04:06:09,314 --> 04:06:12,917
MARKED A SMALL POPULATION OF CES

4579
04:06:12,917 --> 04:06:14,052
THAT YOU COULD FIND IN CHRONIC

4580
04:06:14,052 --> 04:06:15,553
INFECTION AND CANCER.

4581
04:06:15,553 --> 04:06:18,423
AND THAT -- EVEN THOUGH A SMALL

4582
04:06:18,423 --> 04:06:20,625
NUMBER OF CELLS EXPRESSED TCF7,

4583
04:06:20,625 --> 04:06:22,527
WHEN YOU INFECTED MICE, WHAT YOU

4584
04:06:22,527 --> 04:06:30,235
SAW IS OVER TIME, TCF1 DEFICIENT

4585
04:06:30,235 --> 04:06:31,536
CELLS -- SORRY.

4586
04:06:31,536 --> 04:06:33,438
WOULD LOSE THEIR ANTIGEN-SPECIFC

4587
04:06:33,438 --> 04:06:38,243
CELLS AND THEN BE UNABLE TO CLER

4588
04:06:38,243 --> 04:06:38,676
VIRUS.

4589
04:06:38,676 --> 04:06:41,546
AND WHAT BECAME CLEAR IS THAT T7

4590
04:06:41,546 --> 04:06:43,948
MARKED A SMALL POPULATION OF CES

4591
04:06:43,948 --> 04:06:46,818
THAT HAD A PROGENITOR OR STEM-LE

4592
04:06:46,818 --> 04:06:49,153
PHENOTYPE THAT COULD SELF RENEWD

4593
04:06:49,153 --> 04:06:51,122
ALSO DIFFERENTIATE INTO MORE

4594
04:06:51,122 --> 04:06:53,258
EXHAUSTED CELLS AND THIS IS WHAT

4595
04:06:53,258 --> 04:06:56,861
ALLOWED CELLS TO BE MAINTAINED

4596
04:06:56,861 --> 04:06:57,996
DURING CONDITIONS OF EXHAUSTION.

4597
04:06:57,996 --> 04:07:01,566
NOW, IT'S NOW RECOGNIZED FROM WK

4598
04:07:01,566 --> 04:07:04,736
BY MANY PEOPLE THAT TCF1 POSITIE

4599
04:07:04,736 --> 04:07:08,106
CELLS, THEY RESPOND TO PD-1

4600
04:07:08,106 --> 04:07:09,540
BLOCKADE DURING EXHAUSTION.

4601
04:07:09,540 --> 04:07:12,577
WORK FROM ANOTHER LAB SHOWED THT

4602
04:07:12,577 --> 04:07:14,445
TCF7 DEFICIENT CELLS LOOKED LIKE

4603
04:07:14,445 --> 04:07:15,380
TERMINAL EFFECTORS.

4604
04:07:15,380 --> 04:07:17,181
SO WHAT LOOKED LIKE WHAT WE SAWN

4605
04:07:17,181 --> 04:07:19,651
THE ACTIVATED PI3 KINASE MICE.

4606
04:07:19,651 --> 04:07:22,353
WE ASKED, DOES ACTIVATEED PI3

4607
04:07:22,353 --> 04:07:23,955
KINASE DELTA EFFECT THE DEVELOPT

4608
04:07:23,955 --> 04:07:27,358
OF THIS TCF1 PROGENITOR CELL

4609
04:07:27,358 --> 04:07:29,260
POPULATION IN RESPONSE TO CHRONC

4610
04:07:29,260 --> 04:07:30,962
INFECTION AND COULD THIS CONTRIE

4611
04:07:30,962 --> 04:07:33,431
TO THE ALTERED RESPONSES TO CHRC

4612
04:07:33,431 --> 04:07:36,367
INFECTION IN THESE MICE?

4613
04:07:36,367 --> 04:07:38,937
SO TO LOOK AT THAT, WE TOOK A

4614
04:07:38,937 --> 04:07:41,239
CHRONIC INFECTION MODEL WITH LCV

4615
04:07:41,239 --> 04:07:44,842
CLONE 13 WHERE WE COULD LOOK ATE

4616
04:07:44,842 --> 04:07:47,111
PROGENITOR CELLS, THE EXPRESSIOF

4617
04:07:47,111 --> 04:07:49,647
TCF1 AND THEN LOOK AT THE TERMIL

4618
04:07:49,647 --> 04:07:52,150
EXHAUSTED CELLS THAT DIDN'T EXPS

4619
04:07:52,150 --> 04:07:54,886
TCF1 BUT HIGHER LEVELS OF

4620
04:07:54,886 --> 04:07:56,054
EXHAUSTION MARKERS OR INHIBITORY

4621
04:07:56,054 --> 04:07:58,456
RADIOY SEPTEMBERORS SUCH AS TEM.

4622
04:07:58,456 --> 04:08:03,127
AND WHAT WE SAW IS WHEN WE INFED

4623
04:08:03,127 --> 04:08:04,929
THE MICE, YOU COULD SEE JUST LIE

4624
04:08:04,929 --> 04:08:08,866
IN THE ACUTE INFECTION, THAT THE

4625
04:08:08,866 --> 04:08:11,369
GENERATION OF TCF1 POSITIVE

4626
04:08:11,369 --> 04:08:13,972
POPULATION WAS SERIOUSLY IMPAIR.

4627
04:08:13,972 --> 04:08:16,341
IFFY WOO LOOKED BY GENE EXPRESS,

4628
04:08:16,341 --> 04:08:21,045
WHAT WE COULD SEE IS A LOSS OF E

4629
04:08:21,045 --> 04:08:22,447
PROGENITOR-LIKE SIGNATURE, MANYF

4630
04:08:22,447 --> 04:08:24,282
THE GENES THAT WERE ASSOCIATED H

4631
04:08:24,282 --> 04:08:28,152
PROGENITOR TCF1 POSITIVE CELLS.

4632
04:08:28,152 --> 04:08:31,122
HOWEVER, WHEN WE LOOKED AT THE L

4633
04:08:31,122 --> 04:08:34,058
LATERY AND THE RESPONSE, UNLIKE

4634
04:08:34,058 --> 04:08:36,961
TCF1 DEFICIENT MICE OR DEFICIENT

4635
04:08:36,961 --> 04:08:40,231
T-CELLS, WE DID NOT LOSE T-CELL.

4636
04:08:40,231 --> 04:08:42,467
THIS WAS SOMETHING DIFFERENT, A

4637
04:08:42,467 --> 04:08:43,267
RESPONSE LOOKS DIFFERENT.

4638
04:08:43,267 --> 04:08:45,670
YOU COULD TELL THAT EVEN JUST

4639
04:08:45,670 --> 04:08:48,673
LOOKING AT THE MICE BECAUSE UNLE

4640
04:08:48,673 --> 04:08:50,775
TCF1 DEFICIENT MEAS, THESE MICE

4641
04:08:50,775 --> 04:08:52,477
ACTUALLY DID NOT DO WELL.

4642
04:08:52,477 --> 04:08:54,212
MANY OF THEM DIED WITHIN THE FIT

4643
04:08:54,212 --> 04:08:55,780
TWO WEEKS OF INFECTION IF THEY

4644
04:08:55,780 --> 04:08:57,382
SURVIVED THEN THEY MANAGED TO

4645
04:08:57,382 --> 04:08:58,349
CONTINUE ON.

4646
04:08:58,349 --> 04:09:02,153
THEY LOOKED SICKER IN THE FIRST

4647
04:09:02,153 --> 04:09:02,553
WEEK.

4648
04:09:02,553 --> 04:09:10,294
HOWEVER, WHEN WE LET THEM, THE

4649
04:09:10,294 --> 04:09:11,462
SURVIVORS, THEY DID BETTER AND

4650
04:09:11,462 --> 04:09:12,597
GAINED WEIGHT FASTER.

4651
04:09:12,597 --> 04:09:15,366
YOU COULD SEE WITHIN THE FIRST K

4652
04:09:15,366 --> 04:09:17,402
THAT THERE WAS HIGHER VIRAL TITS

4653
04:09:17,402 --> 04:09:20,371
BUT AGAIN THE SURVIVORS WERE ABE

4654
04:09:20,371 --> 04:09:22,173
TO CLEAR THE VIRUS, MUCH BETTER

4655
04:09:22,173 --> 04:09:23,141
THAN WILDTYPE.

4656
04:09:23,141 --> 04:09:28,012
SO SOMETHING ELSE IS GOING ON.

4657
04:09:28,012 --> 04:09:28,479
SO WHAT COULD THAT BE?

4658
04:09:28,479 --> 04:09:31,549
SO THERE IS A HETEROGENEITY OF

4659
04:09:31,549 --> 04:09:32,483
CELLS DURING EXHAUSTION AND THEE

4660
04:09:32,483 --> 04:09:36,220
IS A TCF1 PROGENITOR POPULATIOND

4661
04:09:36,220 --> 04:09:39,090
YOUR MORE TERMINALLY DIFFERENTID

4662
04:09:39,090 --> 04:09:39,891
EXHAUSTED CELLS.

4663
04:09:39,891 --> 04:09:42,193
HOWEVER, IT'S NOW RECOGNIZED FRM

4664
04:09:42,193 --> 04:09:46,931
WORK FROM MULTIPLE GROUPS,

4665
04:09:46,931 --> 04:09:47,465
PARTICULARLY [ INAUDIBLE ]

4666
04:09:47,465 --> 04:09:50,501
THAT THERE IS ALSO THE PRESENCEF

4667
04:09:50,501 --> 04:09:53,905
A KLRG1 POSITIVE CELL POPULATION

4668
04:09:53,905 --> 04:09:56,741
THAT LOOKS MORE LIKE EFFECTOR-LE

4669
04:09:56,741 --> 04:09:59,744
CELL POPULATION, EVEN DURING

4670
04:09:59,744 --> 04:10:00,044
EXHAUSTION.

4671
04:10:00,044 --> 04:10:01,979
AND YOU CAN LOOK AT THOSE CELLSY

4672
04:10:01,979 --> 04:10:07,185
EXPRESSION OF THE MARKER CX3CR1,

4673
04:10:07,185 --> 04:10:09,821
POSITIVE FOR THAT, WHEREAS THE 1

4674
04:10:09,821 --> 04:10:12,824
POSITIVE POPULATION IS IT ALSO

4675
04:10:12,824 --> 04:10:15,493
POSITIVE FOR LIE 108 AND EXHAUSD

4676
04:10:15,493 --> 04:10:17,128
CELLS ARE NEGATIVE FOR BOTH.

4677
04:10:17,128 --> 04:10:18,696
THIS PROVIDES A NICE SYSTEM OF

4678
04:10:18,696 --> 04:10:19,897
MARKERS TO LOOK AT THESE.

4679
04:10:19,897 --> 04:10:23,201
AND SO WHEN WE LOOK AT OUR PI3

4680
04:10:23,201 --> 04:10:25,803
KINASE ACTIVATED MICE, WHAT YOUN

4681
04:10:25,803 --> 04:10:28,806
SEE IS THAT THERE IS A REAL DIRH

4682
04:10:28,806 --> 04:10:32,210
OF THESE PRECURSORS OR PROGENITR

4683
04:10:32,210 --> 04:10:35,780
STEM-LIKE CELLS AND YOU CAN SEE

4684
04:10:35,780 --> 04:10:38,816
THAT MARKED DROP IN THOSE CELLS,

4685
04:10:38,816 --> 04:10:40,785
PARTICULARLY OVER TIME N CONTRA,

4686
04:10:40,785 --> 04:10:43,921
IF YOU LOOK, WE DO GET EXHAUSTED

4687
04:10:43,921 --> 04:10:45,923
CELLS BUT WHAT WE REALLY SEE IS

4688
04:10:45,923 --> 04:10:48,359
THIS LARGE INCREASE IN

4689
04:10:48,359 --> 04:10:50,428
EFFECTOR-LIKE CELL POPULATION TT

4690
04:10:50,428 --> 04:10:51,329
INCREASES OVER TIME.

4691
04:10:51,329 --> 04:10:53,931
SO ACTIVATED PI3 KINASE SEEMS TE

4692
04:10:53,931 --> 04:10:56,734
DRIVING THIS EFFECTOR-LIKE

4693
04:10:56,734 --> 04:10:57,034
POPULATION.

4694
04:10:57,034 --> 04:10:59,637
WE CAN SEE THIS ALSO IF WE LOOKN

4695
04:10:59,637 --> 04:11:02,039
SINGLE CELL RNA-SEQ WHERE THERES

4696
04:11:02,039 --> 04:11:05,376
MANY MORE DIFFERENT POPULATIONS.

4697
04:11:05,376 --> 04:11:08,412
AND WHAT CAN YOU SEE IS THAT YOU

4698
04:11:08,412 --> 04:11:12,817
GET DECREASE IN THESE PROGENITOR

4699
04:11:12,817 --> 04:11:14,619
POPULATIONS WITH INCREASE AND

4700
04:11:14,619 --> 04:11:17,221
EXPANSION OF THESE EFFECTOR CELS

4701
04:11:17,221 --> 04:11:18,956
BUT ALSO AN INCREASE OF MANY OFE

4702
04:11:18,956 --> 04:11:21,726
CELL POPULATIONS THAT ARE EN ROE

4703
04:11:21,726 --> 04:11:24,629
TO TAKING THAT ROUTE TOWARDS THE

4704
04:11:24,629 --> 04:11:27,131
EFFECTOR CELL POPULATION.

4705
04:11:27,131 --> 04:11:30,568
IF WE LOOK SPECIFICALLY AT MARKS

4706
04:11:30,568 --> 04:11:31,636
FOR THESE DIFFERENT CELL

4707
04:11:31,636 --> 04:11:34,172
POPULATIONS, WHAT WE CAN SEE IN

4708
04:11:34,172 --> 04:11:35,439
BOTH OF THE EXHAUSTIVE CELL

4709
04:11:35,439 --> 04:11:37,742
POPULATION AND THE EFFECTOR-LIKE

4710
04:11:37,742 --> 04:11:39,043
POPULATION, IS THAT THEY EXPRESS

4711
04:11:39,043 --> 04:11:41,679
LOWER LEVELS OF MARKERS OF

4712
04:11:41,679 --> 04:11:43,681
EXHAUSTION SO MANY INHIBITORY

4713
04:11:43,681 --> 04:11:46,551
RECEPTORS AS WELL AS THE

4714
04:11:46,551 --> 04:11:48,953
TRANSCRIPTION FACTOR TOX, WHERES

4715
04:11:48,953 --> 04:11:51,255
THEY EXPRESS HIGHER LEVELS OF

4716
04:11:51,255 --> 04:11:54,959
MARKERS FOR EFFECTOR-LIKE CELLSF

4717
04:11:54,959 --> 04:11:55,693
CX.

4718
04:11:55,693 --> 04:12:00,264
THERE CR1 AND R3 AND T BAT AND

4719
04:12:00,264 --> 04:12:00,464
KLRG1.

4720
04:12:00,464 --> 04:12:02,166
WHEN WE STIMULATE THE CELLS, EAH

4721
04:12:02,166 --> 04:12:04,869
THE EXHAUSTED CELLS PRODUCE MORE

4722
04:12:04,869 --> 04:12:05,236
CYTOKINES.

4723
04:12:05,236 --> 04:12:08,539
SO THEY LOOK LIKE THESE CELLS TT

4724
04:12:08,539 --> 04:12:10,074
ARE SUPPOSEDLY EXHAUSTED LOOK LE

4725
04:12:10,074 --> 04:12:13,444
THEY ARE ACTUALLY NOW FUNCTIONAN

4726
04:12:13,444 --> 04:12:14,178
THESE MICE.

4727
04:12:14,178 --> 04:12:18,149
SO ARE THESE PHENOTYPES CD8 T-CL

4728
04:12:18,149 --> 04:12:20,151
INTRINSIC OR DUE TO INTERACTIONS

4729
04:12:20,151 --> 04:12:21,052
FROM OTHER CELLS?

4730
04:12:21,052 --> 04:12:23,454
TO ASK THAT QUESTION, WE TOOK

4731
04:12:23,454 --> 04:12:26,557
ADVANTAGE OF THE P14 TRANSGENIC

4732
04:12:26,557 --> 04:12:28,960
SYSTEM WHICH WAS SPECIFIC FOR TE

4733
04:12:28,960 --> 04:12:31,562
MAJOR EPITOPE PLUS ONE RESTRICTD

4734
04:12:31,562 --> 04:12:33,064
EPITOPE ON LCMV.

4735
04:12:33,064 --> 04:12:35,866
WE COULD TAKE P14 CELLS MUTANT R

4736
04:12:35,866 --> 04:12:38,970
PI3 KINASE OR WILDTYPE, MIX THEM

4737
04:12:38,970 --> 04:12:40,071
ONE-TO-ONE AND WITHOUT THEM INTA

4738
04:12:40,071 --> 04:12:43,474
HOST SO WE ARE LOOKING AT THE

4739
04:12:43,474 --> 04:12:44,275
RESPONSES IN THE SAME BACKGROUN.

4740
04:12:44,275 --> 04:12:47,078
SO WE ARE NOT BEING CONFOUNDED Y

4741
04:12:47,078 --> 04:12:48,646
DIFFERENCES IN VIRAL TITER.

4742
04:12:48,646 --> 04:12:51,582
AND WHAT CAN YOU SEE IS, CLEARLY

4743
04:12:51,582 --> 04:12:56,153
HAVE THE CELL INTRINSIC LOSS INE

4744
04:12:56,153 --> 04:12:57,989
PRECURSOR OR PROGENITOR EXHAUSTD

4745
04:12:57,989 --> 04:12:59,590
CELLS, VERY CLEARLY MARKED HERE.

4746
04:12:59,590 --> 04:13:01,892
WE DO SEE SOME INCREASE IN THE

4747
04:13:01,892 --> 04:13:02,960
EFFECTOR-LIKE CELLS ALTHOUGH ITS

4748
04:13:02,960 --> 04:13:05,329
NOT AS DRAMATIC.

4749
04:13:05,329 --> 04:13:07,898
SO WHY ARE WE LOSING THOSE CELL?

4750
04:13:07,898 --> 04:13:12,603
SO TCF7 EXPRESSION IS DRIVEN IN

4751
04:13:12,603 --> 04:13:14,205
EXHAUSTED CELLS IN LARGE PART

4752
04:13:14,205 --> 04:13:16,440
THROUGH THE TRANSCRIPTION FACTOR

4753
04:13:16,440 --> 04:13:19,210
FOX 01 AND THAT TRANSCRIPTION FT

4754
04:13:19,210 --> 04:13:22,713
ON ARE IS UPACTIVATED DOWNSTREAF

4755
04:13:22,713 --> 04:13:24,782
PI3 KINASE -- INACTIVATED.

4756
04:13:24,782 --> 04:13:29,854
IN WE TAKE CELLS, WE CAN TAKE

4757
04:13:29,854 --> 04:13:32,590
WILDTYPE P14 CELLS AND WE CAN UE

4758
04:13:32,590 --> 04:13:35,693
CHRIS PER TO KNOCKOUT -- CRISPR-

4759
04:13:35,693 --> 04:13:38,229
FOX 01 IN NAIVE CD4 CELLS, TRANR

4760
04:13:38,229 --> 04:13:39,930
THEM INTO A MOUSE AND THEN INFET

4761
04:13:39,930 --> 04:13:42,233
THEM WITH LCMV13.

4762
04:13:42,233 --> 04:13:45,036
YOU CAN SEE THAT FOX 01 KNOCKOUS

4763
04:13:45,036 --> 04:13:47,104
VERY NICE HERE AND YOU CAN SEE T

4764
04:13:47,104 --> 04:13:49,240
LEADS TO A LOSS OF EXPRESSION OF

4765
04:13:49,240 --> 04:13:50,841
MOST OF THE TCF1.

4766
04:13:50,841 --> 04:13:52,276
WHEN WE DO THAT, WHAT YOU SEE IS

4767
04:13:52,276 --> 04:13:54,745
THAT YOU CAN RECAPITULATE VERY

4768
04:13:54,745 --> 04:13:57,648
NICELY THAT DRAMATIC LOSS IN THE

4769
04:13:57,648 --> 04:13:59,417
PROGENITOR CELL POPULATION.

4770
04:13:59,417 --> 04:14:01,052
HOWEVER, WE DON'T RECAPITULATE E

4771
04:14:01,052 --> 04:14:04,255
INCREASE IN EFFECTOR CELLS.

4772
04:14:04,255 --> 04:14:06,857
SO FOX 01 INACTIVATION IS

4773
04:14:06,857 --> 04:14:09,160
RESPONSIBLE FOR THE LOSS OF THE

4774
04:14:09,160 --> 04:14:10,728
TCF1 POSITIVE POPULATION.

4775
04:14:10,728 --> 04:14:11,962
PROGENITOR POPULATION, BUT NOT R

4776
04:14:11,962 --> 04:14:14,532
THE INCREASE IN EFFECTORS.

4777
04:14:14,532 --> 04:14:16,434
NOW WE ALSO LOOK TO SEE IF THERE

4778
04:14:16,434 --> 04:14:18,235
WERE CELL EXTRINSIC EFFECTS.

4779
04:14:18,235 --> 04:14:23,074
TO DO THAT, WE HAD TO TAKE WILDE

4780
04:14:23,074 --> 04:14:24,742
P14CD8 CELLS AND THANS FER THEM

4781
04:14:24,742 --> 04:14:27,244
INTO WILDTYPE OR MUTANT HOSTS.

4782
04:14:27,244 --> 04:14:30,648
AND THEN WHAT WE COULD SEE IS T,

4783
04:14:30,648 --> 04:14:32,750
THERE WERE ALSO CELL EXTRINSIC

4784
04:14:32,750 --> 04:14:33,951
ASPECTS TO THIS PHENOTYPE.

4785
04:14:33,951 --> 04:14:37,888
SO THEY ARE NOT ALL CD8 CELL

4786
04:14:37,888 --> 04:14:38,189
INTRINSIC.

4787
04:14:38,189 --> 04:14:40,458
WE SAW SOME REDUCTION IN THE

4788
04:14:40,458 --> 04:14:43,160
PROGENITORS BUT WE SAW THIS LARE

4789
04:14:43,160 --> 04:14:44,762
INCREASE IN THE EFFECTOR-LIKE

4790
04:14:44,762 --> 04:14:45,129
CELLS.

4791
04:14:45,129 --> 04:14:46,864
AND SO WHY IS THAT?

4792
04:14:46,864 --> 04:14:49,166
WHAT ARE THE POTENTIAL CELL

4793
04:14:49,166 --> 04:14:49,767
EXTRINSIC EFFECTS?

4794
04:14:49,767 --> 04:14:52,470
COULD IT BE OTHER T-CELLS, T

4795
04:14:52,470 --> 04:14:52,737
REGULARS?

4796
04:14:52,737 --> 04:14:57,475
IT'S BEEN SHOWN THAT INHIBITING

4797
04:14:57,475 --> 04:14:59,910
THESE CELLS BLOCKS T-REG FUNCTI.

4798
04:14:59,910 --> 04:15:00,845
THAT'S THE OPPOSITE.

4799
04:15:00,845 --> 04:15:03,381
WE FOCUSED ON WHAT CYTOKINES MIT

4800
04:15:03,381 --> 04:15:04,682
BE PRODUCED IN THESE MICE.

4801
04:15:04,682 --> 04:15:06,684
WHAT WE SAW IS THAT IN FACT IN

4802
04:15:06,684 --> 04:15:08,586
RESPONSE TO LCMV, WE COULD SEE

4803
04:15:08,586 --> 04:15:10,688
LARGE INCREASES IN A NUMBER OF

4804
04:15:10,688 --> 04:15:14,291
CYTOKINES AND PARTICULARLY WE HD

4805
04:15:14,291 --> 04:15:15,025
INTO IL21.

4806
04:15:15,025 --> 04:15:17,294
AND PREVIOUS DATA SHOWN THAT IL1

4807
04:15:17,294 --> 04:15:20,498
IS VERY POTENT IN INDUCING EFFER

4808
04:15:20,498 --> 04:15:23,501
CELL CD8 CELL FUNCTION AND

4809
04:15:23,501 --> 04:15:24,034
SURVIVAL.

4810
04:15:24,034 --> 04:15:27,705
AND MORE RECENT WORK FROM ANOTHR

4811
04:15:27,705 --> 04:15:30,107
LAB HAD SHOWN THAT TFH CELLS ARE

4812
04:15:30,107 --> 04:15:32,610
THAT SOURCE OF IL21 THAT CAN LED

4813
04:15:32,610 --> 04:15:35,413
TO THE GENERATION OF THESE EFFER

4814
04:15:35,413 --> 04:15:37,181
CD8 CELLS UNDER CONDITIONS OF

4815
04:15:37,181 --> 04:15:37,481
EXHAUSTION.

4816
04:15:37,481 --> 04:15:39,717
AND SO IF WE LOOK AT OUR MICE, T

4817
04:15:39,717 --> 04:15:42,820
WE SEE IS THERE ARE -- THERE ISN

4818
04:15:42,820 --> 04:15:47,625
INCREASE IN TFH CELLS OR ANNUAL

4819
04:15:47,625 --> 04:15:50,961
JEN-SPECIFIC TFH CELLS.

4820
04:15:50,961 --> 04:15:53,431
SO TO SEE IF THAT WAS IMPORTANTE

4821
04:15:53,431 --> 04:15:55,466
DID THE SAME INFECTION WITH LCMN

4822
04:15:55,466 --> 04:15:58,936
THE PRESENCE OF BLOCKING ANTI-I1

4823
04:15:58,936 --> 04:16:02,239
RECEPTOR ANTIBODIES OR DEPLETING

4824
04:16:02,239 --> 04:16:04,141
ANTI-CD4 MONOCLONAL ANTIBODIES.

4825
04:16:04,141 --> 04:16:05,609
WHAT WE COULD CLEARLY SEE IS THT

4826
04:16:05,609 --> 04:16:08,212
IF YOU LOOK AT THAT LARGE INCREE

4827
04:16:08,212 --> 04:16:11,749
IN EFFECTOR CELLS IN THE MUTANT

4828
04:16:11,749 --> 04:16:14,185
MICE, THAT WAS LARGELY ABROGATED

4829
04:16:14,185 --> 04:16:18,122
WHEN WE BLOCKED IL21 RECEPTOR, O

4830
04:16:18,122 --> 04:16:26,530
PRETTY WELL BLOCKED BY ANTI-CD4.

4831
04:16:26,530 --> 04:16:29,533
SO, WHAT ABOUT THE RESPONSE TO

4832
04:16:29,533 --> 04:16:29,834
IL21?

4833
04:16:29,834 --> 04:16:32,837
SO WE TOOK ISOLATED CD8 CELLS FM

4834
04:16:32,837 --> 04:16:34,071
THESE MICE AND STIMULATED THEM N

4835
04:16:34,071 --> 04:16:37,541
THE PRESENCE OF IL21 OR STIMULAD

4836
04:16:37,541 --> 04:16:41,479
THEM AND ADDED IL21.

4837
04:16:41,479 --> 04:16:44,482
WE SAW THAT THE MUTANTS IN YELLW

4838
04:16:44,482 --> 04:16:47,351
SHOWED HIGHER LEVELS OF PHOSPHOT

4839
04:16:47,351 --> 04:16:50,087
3, DOWNSTREAM OF IL21 RECEPTOR D

4840
04:16:50,087 --> 04:16:54,191
ALSO SHOWED A GREATER INDUCTIONF

4841
04:16:54,191 --> 04:16:54,425
CX3CR1.

4842
04:16:54,425 --> 04:16:57,394
SO YOU WOULD THINK THIS IS A CEL

4843
04:16:57,394 --> 04:17:00,097
INTRINSIC EFFECT OF THIS.

4844
04:17:00,097 --> 04:17:02,600
AND SO, DOES THAT ARGUE -- IS TE

4845
04:17:02,600 --> 04:17:04,802
AN ALTER DEVELOPMENTAL PATHWAY?

4846
04:17:04,802 --> 04:17:06,770
ARE THESE CELLS INTRINSICALLY

4847
04:17:06,770 --> 04:17:06,971
PRONE?

4848
04:17:06,971 --> 04:17:10,474
SO TO DO THAT, WE INFECTED THE

4849
04:17:10,474 --> 04:17:12,209
MYSELF, SORTED OUT PROGENITOR

4850
04:17:12,209 --> 04:17:14,812
CELLS, TRANSFERRED THEM INTO

4851
04:17:14,812 --> 04:17:16,013
INFECTION MATCHED HOSTS AND LOOD

4852
04:17:16,013 --> 04:17:18,215
AT THE PROGENY A WEEK LATER.

4853
04:17:18,215 --> 04:17:21,719
THE WILDTYPE PRECURSOR CELLS, MT

4854
04:17:21,719 --> 04:17:23,821
STAYED AS PROGENITOR OR PRECURSR

4855
04:17:23,821 --> 04:17:27,157
BUT A LARGE FRACTION OF THEM ALO

4856
04:17:27,157 --> 04:17:28,125
BECAME TERMINALLY EXHAUSTED CEL.

4857
04:17:28,125 --> 04:17:31,529
THE MUTANT PROGENITOR CELLS, VEY

4858
04:17:31,529 --> 04:17:33,464
FEW OF THEM STAYED AS PROGENITOR

4859
04:17:33,464 --> 04:17:35,332
AND MAINLY BECAME EFFECTOR-LIKE

4860
04:17:35,332 --> 04:17:35,533
CELLS.

4861
04:17:35,533 --> 04:17:39,403
SO ACTIVATED PI3 KINASES IS

4862
04:17:39,403 --> 04:17:41,338
PROPELLING THESE CELLS TO BECOME

4863
04:17:41,338 --> 04:17:43,541
EFFECTOR-LIKE CELLS.

4864
04:17:43,541 --> 04:17:45,643
SO IN WILDTYPE BACKGROUND YOU SE

4865
04:17:45,643 --> 04:17:47,711
MULTIPLE CD8 CELL POPULATIONS

4866
04:17:47,711 --> 04:17:50,848
DURING CHRONIC INFECTION BUT THY

4867
04:17:50,848 --> 04:17:53,951
ARE ALTERED IN ACTIVATED PI3

4868
04:17:53,951 --> 04:17:54,218
KINASE.

4869
04:17:54,218 --> 04:17:56,554
SO FEWER PROGENITOR CELLS

4870
04:17:56,554 --> 04:17:58,322
PRESUMABLY YOU WOULD GET POORER

4871
04:17:58,322 --> 04:17:59,657
RESPONSES TO ICB.

4872
04:17:59,657 --> 04:18:02,192
BUT AT THE SAME TIME YOU GET

4873
04:18:02,192 --> 04:18:09,166
INCREASED VIRAL AND TUMOR -- SO.

4874
04:18:09,166 --> 04:18:09,934
INCREASED EFFECTOR CELLS WHICH

4875
04:18:09,934 --> 04:18:12,036
PRESUMABLY WILL LEAD TO INCREASD

4876
04:18:12,036 --> 04:18:13,971
VIRAL AND TUMOR CLEARANCE.

4877
04:18:13,971 --> 04:18:18,342
SO IS PI3 KINASE GOOD OR BAD FOR

4878
04:18:18,342 --> 04:18:18,642
EXHAUSTION?

4879
04:18:18,642 --> 04:18:21,979
I THINK THE JURY IS OUT AND THAS

4880
04:18:21,979 --> 04:18:24,548
BECAUSE IT EFFECTS BOTH CELL

4881
04:18:24,548 --> 04:18:25,049
POPULATIONS.

4882
04:18:25,049 --> 04:18:27,451
SO IF YOU HAVE LITTLE PI3 KINASE

4883
04:18:27,451 --> 04:18:29,186
ACTIVITY, IF YOU INHIBIT IT, YOU

4884
04:18:29,186 --> 04:18:31,255
PROMOTE THOSE PROGENITOR CELLS T

4885
04:18:31,255 --> 04:18:32,957
YOU WANT FOR CHECKPOINT BLOCKAD.

4886
04:18:32,957 --> 04:18:35,826
IT ALSO IS VERY GOOD FOR CURBING

4887
04:18:35,826 --> 04:18:37,561
T-REG ACTIVITY HOWEVER, ACTIVATN

4888
04:18:37,561 --> 04:18:40,064
OF PI3 KINASE IS REALLY IMPORTAT

4889
04:18:40,064 --> 04:18:42,299
FOR PROMOTING EFFECTOR-LIKE CELS

4890
04:18:42,299 --> 04:18:45,069
AND THAT IS PART OF WHAT PD-1 BK

4891
04:18:45,069 --> 04:18:48,472
AID DOES, IS TO ACTIVATE PI3 KIE

4892
04:18:48,472 --> 04:18:48,739
PATHWAYS.

4893
04:18:48,739 --> 04:18:50,274
AND SO, IT'S VERY INTERESTING TN

4894
04:18:50,274 --> 04:18:52,276
THE LAST YEAR, A PAPER CAME OUT

4895
04:18:52,276 --> 04:18:54,979
THAT INTERMITTENT PI3 KINASE

4896
04:18:54,979 --> 04:18:57,081
INHIBITION WAS VERY GOOD FOR

4897
04:18:57,081 --> 04:18:58,349
SUSTAINING ANTI-TUMOR IMMUNITY.

4898
04:18:58,349 --> 04:19:02,786
THAT WAS FOCUSED ON T-REGS BUT

4899
04:19:02,786 --> 04:19:04,888
PERHAPS ALSO EFFECTS ON CD8 CELS

4900
04:19:04,888 --> 04:19:05,889
AND CERTAINLY SUGGESTS THAT YOU

4901
04:19:05,889 --> 04:19:07,558
NEED TO THINK ABOUT THESE BALANS

4902
04:19:07,558 --> 04:19:09,893
AS YOU'RE TRYING TO BALANCE BOTH

4903
04:19:09,893 --> 04:19:13,297
THE PROTECTED AND THE DETRIMENTL

4904
04:19:13,297 --> 04:19:13,931
EFFECTS OF EXHAUSTION.

4905
04:19:13,931 --> 04:19:16,033
AND THIS WAS RELATED TO THE WORF

4906
04:19:16,033 --> 04:19:21,005
A TALENTED FELLOW WHO IS IN THE

4907
04:19:21,005 --> 04:19:23,874
AUDIENCE WITH HELP FROM OTHERS.

4908
04:19:23,874 --> 04:19:25,943
THANK YOU.

4909
04:19:25,943 --> 04:19:36,086
[ APPLAUSE ]

4910
04:19:36,086 --> 04:19:37,321
>> THANK YOU, QUESTION?

4911
04:19:37,321 --> 04:19:37,788
>> BEAUTIFUL TALK.

4912
04:19:37,788 --> 04:19:39,923
I HAVE A VERY NICE QUESTION.

4913
04:19:39,923 --> 04:19:41,558
WOULD YOU EXPECT THE SAME TO HAN

4914
04:19:41,558 --> 04:19:45,329
ALSO IN A TUMOR MODEL IN THESE

4915
04:19:45,329 --> 04:19:45,629
MICE?

4916
04:19:45,629 --> 04:19:47,731
>> SO WE HAVE BEEN
STARTING TO K

4917
04:19:47,731 --> 04:19:50,434
AT IT AND ALSO OTHER GROUPS HAVE

4918
04:19:50,434 --> 04:19:52,336
TOO, AND IT DEPENDS ON THE TUMOR

4919
04:19:52,336 --> 04:19:54,538
MODEL AND IT MAY DEPEND ON WHAT

4920
04:19:54,538 --> 04:19:55,439
YOU'RE DOING.

4921
04:19:55,439 --> 04:20:00,144
AND SO SOME OF THIS -- TREATINGR

4922
04:20:00,144 --> 04:20:03,681
NOT TREATING MAY -- FOR EXAMPLEN

4923
04:20:03,681 --> 04:20:05,516
ADOPTED CELL THERAPY-TYPE MODEL,

4924
04:20:05,516 --> 04:20:09,053
PERHAPS YOU WANT TO INHIBIT PI3

4925
04:20:09,053 --> 04:20:10,320
KINASE BUT YOU DON'T WANT TO DO

4926
04:20:10,320 --> 04:20:11,555
THAT IN-VIVO.

4927
04:20:11,555 --> 04:20:13,524
SO IT MAY DEPEND ON THE TISSUE D

4928
04:20:13,524 --> 04:20:18,429
THE TYPE OF TUMOR.

4929
04:20:18,429 --> 04:20:21,432
>> I READ SOMEWHERE THE
SIZE WAS

4930
04:20:21,432 --> 04:20:23,534
EXPRESSED IN THE BRAIN.

4931
04:20:23,534 --> 04:20:26,336
EITHER PATIENTS OR MICE SHOW ANY

4932
04:20:26,336 --> 04:20:28,706
NEURONAL EFFECTS?

4933
04:20:28,706 --> 04:20:30,040
>> YES, SO MANY THINGS ARE

4934
04:20:30,040 --> 04:20:33,243
EXPRESSED IN THE BRAIN.

4935
04:20:33,243 --> 04:20:35,846
AND WE HAVE NOT DETECTED IT BUTE

4936
04:20:35,846 --> 04:20:39,149
HAVE NOT PUT MICE THROUGH VARIOS

4937
04:20:39,149 --> 04:20:41,552
CHALLENGES TO ACTUALLY FIND OUTF

4938
04:20:41,552 --> 04:20:43,053
THEY ARE SMART OR DUMB.

4939
04:20:43,053 --> 04:20:45,055
BUT WHETHER THE INHIBITORS EFFET

4940
04:20:45,055 --> 04:20:47,091
THE BRAIN -- INHIBITORS HAVE BEN

4941
04:20:47,091 --> 04:20:51,762
USED IN TUMORS IN PATIENTS AND I

4942
04:20:51,762 --> 04:20:53,297
DON'T THINK THAT'S BEEN LOOKED .

4943
04:20:53,297 --> 04:20:55,032
THERE HAS BEEN OTHER PROBLEMS WH

4944
04:20:55,032 --> 04:21:01,305
ALTERNATE IMMUNITY AND T-REGS.

4945
04:21:01,305 --> 04:21:04,975
>> THERE IS NO KIND OF --
[

4946
04:21:04,975 --> 04:21:05,275
INAUDIBLE ]

4947
04:21:05,275 --> 04:21:05,642
>> I'M SORRY.

4948
04:21:05,642 --> 04:21:06,977
THAT'S A GREAT QUESTION.

4949
04:21:06,977 --> 04:21:13,183
THE PATIENTS ARE COGNITIVELY ARE

4950
04:21:13,183 --> 04:21:14,351
FINE.

4951
04:21:14,351 --> 04:21:15,586
>> GREAT TALK.

4952
04:21:15,586 --> 04:21:17,588
SORRY IF YOU SAID THIS AND I MID

4953
04:21:17,588 --> 04:21:17,755
IT.

4954
04:21:17,755 --> 04:21:21,558
IS THERE ANY CHANGE IN

4955
04:21:21,558 --> 04:21:21,892
FOXEXPRESSION?

4956
04:21:21,892 --> 04:21:24,194
>> FOXEXPRESSION IS DOWN.

4957
04:21:24,194 --> 04:21:25,796
-- TOX EXPRESSION IS DOWN.

4958
04:21:25,796 --> 04:21:28,632
IT GOES ALONG WITH THEM BEING LS

4959
04:21:28,632 --> 04:21:28,932
EXHAUSTIVE.

4960
04:21:28,932 --> 04:21:36,240
>> THANK YOU.

4961
04:21:36,240 --> 04:21:36,707
>> SO [ INAUDIBLE ]

4962
04:21:36,707 --> 04:21:38,842
 AGREED TO STAND IN WITH US ANDS

4963
04:21:38,842 --> 04:21:49,219
GOING TO INTRODUCE --

4964
04:22:44,408 --> 04:22:45,742
>> IT GIVES ME A LOT OF
PLEASURO

4965
04:22:45,742 --> 04:22:48,645
BE ABLE TO INTRODUCE STANLEY ADO

4966
04:22:48,645 --> 04:22:52,883
WHO IS A HOMETOWN HERO FROM THE

4967
04:22:52,883 --> 04:22:54,918
CENTER FOR CANCER RESEARCH HERET

4968
04:22:54,918 --> 04:22:55,352
NCI.

4969
04:22:55,352 --> 04:22:57,721
HE IS GOING TO BE TALKING TO US

4970
04:22:57,721 --> 04:23:01,391
ABOUT PROTEOSTASIS AND ITS LINKO

4971
04:23:01,391 --> 04:23:02,759
T-CELL AUTONOMOUS DYSFUNCTION.

4972
04:23:02,759 --> 04:23:08,031
THANK YOU, STANLEY.

4973
04:23:08,031 --> 04:23:11,235
>> I THINK EVERYONE CAN
HEAR ME,

4974
04:23:11,235 --> 04:23:11,435
RIGHT?

4975
04:23:11,435 --> 04:23:12,936
I WOULD LIKE TO THANK THE

4976
04:23:12,936 --> 04:23:13,804
ORGANIZERS FOR THE CHANCE TO

4977
04:23:13,804 --> 04:23:16,139
PRESENT THE WORK FROM MY LAB.

4978
04:23:16,139 --> 04:23:20,644
AND I ALSO WANT TO THANK THEM FR

4979
04:23:20,644 --> 04:23:23,947
GETTING STARTED IN THE EXHAUSTIN

4980
04:23:23,947 --> 04:23:24,281
CONVERSATION.

4981
04:23:24,281 --> 04:23:27,351
TODAY I'D LIKE TO SHARE WITH YOU

4982
04:23:27,351 --> 04:23:30,520
SOME UNPUBLISHED WORK FROM A

4983
04:23:30,520 --> 04:23:37,861
TALENTED GRAD STUDENT FROM MY L.

4984
04:23:37,861 --> 04:23:43,533
WE THINK THE KEY -- MAY PLAY A Y

4985
04:23:43,533 --> 04:23:45,435
IMPORTANT ROLE IN THE PROGRAM TT

4986
04:23:45,435 --> 04:23:50,607
MAY CONTRIBUTE TO CELL EXHAUSTI.

4987
04:23:50,607 --> 04:23:52,743
SO, YOU HAD ENOUGH BACKGROUND ON

4988
04:23:52,743 --> 04:23:53,810
EXHAUSTION SO I WANT TO GET YOU

4989
04:23:53,810 --> 04:23:56,546
INTO REALLY THE PROGRAM I WANT O

4990
04:23:56,546 --> 04:24:02,853
TALK ABOUT TODAY, THE -- MY LABS

4991
04:24:02,853 --> 04:24:06,156
INTERESTED IN HOW -- CONTRIBUTEO

4992
04:24:06,156 --> 04:24:07,958
IMMUNE CELL DIFFERENTIATION AND

4993
04:24:07,958 --> 04:24:08,225
FUNCTION.

4994
04:24:08,225 --> 04:24:09,660
THERE ARE MANY OF THESE PATHWAYS

4995
04:24:09,660 --> 04:24:12,329
BUT ISLAND LIKE TO FOCUS ON THE

4996
04:24:12,329 --> 04:24:13,196
PROTEIN RESPONSE.

4997
04:24:13,196 --> 04:24:15,666
SO FOR THIS, IF WE DON'T THINK

4998
04:24:15,666 --> 04:24:17,434
ABOUT UPR ALL THE TIME.

4999
04:24:17,434 --> 04:24:19,336
THERE ARE THREE ENZYMES.

5000
04:24:19,336 --> 04:24:25,642
THEY ARE PLASMA MEMBRANE ENZYMEO

5001
04:24:25,642 --> 04:24:28,445
THESE ENZYMES ARE THOUGHT TO BE

5002
04:24:28,445 --> 04:24:29,646
ENACTED AND THE ACTIVATION IS

5003
04:24:29,646 --> 04:24:33,951
DRIVEN BY THE ASSOCIATION WITH

5004
04:24:33,951 --> 04:24:36,653
THE -- THEY GET ACTIVATED, THE

5005
04:24:36,653 --> 04:24:40,524
CURRENT MODEL IS WHEN THE PROTES

5006
04:24:40,524 --> 04:24:44,861
ARE IN THE LUMEN AND THERE --

5007
04:24:44,861 --> 04:24:47,564
HIGHER ASSOCIATION, AFFINITY FOR

5008
04:24:47,564 --> 04:24:51,868
MISFOLDED PROTEINS SUCH THAT ONE

5009
04:24:51,868 --> 04:24:55,072
YOU HAVE -- THESENCE ZYME, THEY

5010
04:24:55,072 --> 04:24:57,174
LEAD TO ACTIVATION.

5011
04:24:57,174 --> 04:24:57,975
-- THESE ENZYMES.

5012
04:24:57,975 --> 04:24:59,142
YOU DON'T HAVE TO REMEMBER WHATS

5013
04:24:59,142 --> 04:25:01,545
ON THIS SLIDE BUT THE TAKE-HOME

5014
04:25:01,545 --> 04:25:04,581
MESSAGE IS THOSE THREE ENZYMES A

5015
04:25:04,581 --> 04:25:08,885
SET OF FACTORS THAT ACTIVATE

5016
04:25:08,885 --> 04:25:16,526
DOWNSTREAM PROGRAM.

5017
04:25:16,526 --> 04:25:17,361
SO [ INAUDIBLE ]

5018
04:25:17,361 --> 04:25:19,763
ATF6 IS PROCESSED IS ACTUALLY

5019
04:25:19,763 --> 04:25:21,765
TRANSCRIPTION FACTOR.

5020
04:25:21,765 --> 04:25:30,774
SO THESE THREE ENZYMES -- DRIVE

5021
04:25:30,774 --> 04:25:31,375
DOWNSTREAM FUNCTION.

5022
04:25:31,375 --> 04:25:36,480
I WANT TO POINT OUT HERE THAT TE

5023
04:25:36,480 --> 04:25:39,683
THREE FACTORS ARE ALL -- PROTEI.

5024
04:25:39,683 --> 04:25:47,190
AND IN MY TALK, THAT IS ACTUALL-

5025
04:25:47,190 --> 04:25:47,691
DECISION.

5026
04:25:47,691 --> 04:25:49,292
CLASSICALLY THE EPR IS KNOWN TO

5027
04:25:49,292 --> 04:25:51,895
TURN ON PROGRAMS THAT WILL PROME

5028
04:25:51,895 --> 04:25:55,699
PROTEIN FOLDING BECAUSE THAT'S T

5029
04:25:55,699 --> 04:25:58,635
IT'S EVOLVED TO DO.

5030
04:25:58,635 --> 04:26:01,772
SOME OF THESE TARGETS EXTEND BED

5031
04:26:01,772 --> 04:26:04,207
CLASSICAL PROTEIN HOMEOSTASIS

5032
04:26:04,207 --> 04:26:04,474
PROGRAM.

5033
04:26:04,474 --> 04:26:08,078
SO WE GOT INTERESTED ON WHAT WE-

5034
04:26:08,078 --> 04:26:11,581
QUESTION HOW IT MAY -- T-CELL

5035
04:26:11,581 --> 04:26:11,948
DIFFERENTIATION.

5036
04:26:11,948 --> 04:26:16,987
SO T-CELLS ARE ACTIVATED AND THY

5037
04:26:16,987 --> 04:26:18,789
ARE TURNED -- VERY EARLY.

5038
04:26:18,789 --> 04:26:23,093
HOWEVER, THE LITERATURE OUT THEE

5039
04:26:23,093 --> 04:26:25,595
IS AT BEST, CONTRADICTORY IN THE

5040
04:26:25,595 --> 04:26:27,497
SENSE THAT THERE IS SOME STUDIES

5041
04:26:27,497 --> 04:26:29,900
USING INDIVIDUAL SINGLE KNOCKOUS

5042
04:26:29,900 --> 04:26:31,902
OF THESE ENZYMES IN T-CELLS THAT

5043
04:26:31,902 --> 04:26:35,772
SUGGEST THEY ARE DISPENSABLE FOR

5044
04:26:35,772 --> 04:26:36,873
T-CELL DIFFERENTIATION.

5045
04:26:36,873 --> 04:26:41,611
OR SURPRISINGLY THESE ENZYMES CD

5046
04:26:41,611 --> 04:26:43,080
PROMOTE IMMUNOSUPPRESSION BY

5047
04:26:43,080 --> 04:26:43,313
T-CELLS.

5048
04:26:43,313 --> 04:26:45,415
ONE THING THAT HAS BEEN OVERLOO,

5049
04:26:45,415 --> 04:26:48,118
YOU HAVE THREE ENZYMES, IS IT

5050
04:26:48,118 --> 04:26:50,020
POSSIBLE THEY FUNCTION REDUNDAN?

5051
04:26:50,020 --> 04:26:51,922
THE QUESTION I WANTED TO ADDRESS

5052
04:26:51,922 --> 04:26:54,724
WAS, IS THERE REDUNDANCY IN THER

5053
04:26:54,724 --> 04:26:55,292
SIGNALING PROGRAM?

5054
04:26:55,292 --> 04:26:59,729
IF SO, WHAT IS THE CONSEQUENCE F

5055
04:26:59,729 --> 04:27:02,032
UPR DEFICIENCY?

5056
04:27:02,032 --> 04:27:04,701
SO TO ADDRESS THAT, THE MOUSE ML

5057
04:27:04,701 --> 04:27:10,440
IN WHICH WE USE CD4 TO REMOVE TE

5058
04:27:10,440 --> 04:27:12,609
ENZYMES, THESE MICE LACK ALL THE

5059
04:27:12,609 --> 04:27:13,710
SENSORS.

5060
04:27:13,710 --> 04:27:17,514
WE CALL THEM UPR KNOCKOUT ANIMA.

5061
04:27:17,514 --> 04:27:21,518
WHEN WE KNOCK IT OUT FROM T-CEL,

5062
04:27:21,518 --> 04:27:25,122
T-CELL DEVELOPMENT IS FINE --

5063
04:27:25,122 --> 04:27:27,124
SO THE QUESTION WE WANTED TO GET

5064
04:27:27,124 --> 04:27:30,427
IS, HOW DOES THIS IMPACT T-CELL

5065
04:27:30,427 --> 04:27:34,798
EFFECTOR DIFFERENTIATION?

5066
04:27:34,798 --> 04:27:36,032
CONTRARY TO -- I'M GOING TO BE

5067
04:27:36,032 --> 04:27:38,935
USING THE ARMSTRONG MODEL.

5068
04:27:38,935 --> 04:27:41,404
THAT MODEL IS AN ACTIVE INFECTIN

5069
04:27:41,404 --> 04:27:51,781
MODEL THAT IS RESOLVED AROUND T[

5070
04:27:51,781 --> 04:27:52,382
INAUDIBLE ]

5071
04:27:52,382 --> 04:27:52,782
AND MAMMARY CELLS.

5072
04:27:52,782 --> 04:27:54,351
WE ASKED THE QUESTION, WHAT HAPS

5073
04:27:54,351 --> 04:27:58,955
WHEN WE INFECT WILDTYPE AND UPR

5074
04:27:58,955 --> 04:28:00,724
KNOCKOUT ANIMALS WITH ARMSTRONG?

5075
04:28:00,724 --> 04:28:02,926
WHAT CAN YOU APPRECIATE HERE IS

5076
04:28:02,926 --> 04:28:05,328
THAT AT THE AGE WHEN MOST OF THE

5077
04:28:05,328 --> 04:28:09,332
WILDTYPE ANIMALS HAVE SIGNIFICAY

5078
04:28:09,332 --> 04:28:11,334
CLEARED THE VIRUS, THERE IS A HE

5079
04:28:11,334 --> 04:28:15,238
AMOUNT OF VIRUS IN THE KNOCKOUTN

5080
04:28:15,238 --> 04:28:18,642
THE T-CELLS -- UNABLE TO RESOLVE

5081
04:28:18,642 --> 04:28:21,077
THIS ACUTE INFECTION.

5082
04:28:21,077 --> 04:28:22,546
WHY IS THAT?

5083
04:28:22,546 --> 04:28:25,749
SO WE LOOKED AT THE MODEL CLOSEY

5084
04:28:25,749 --> 04:28:31,721
AND YOU SEE -- GENERATE SPECIFIC

5085
04:28:31,721 --> 04:28:35,025
T-CELLS BUT IN NUMBERS AND

5086
04:28:35,025 --> 04:28:36,560
FREQUENCY -- NUMBERS SIGNIFICANY

5087
04:28:36,560 --> 04:28:37,861
ARE DEPLETED.

5088
04:28:37,861 --> 04:28:42,566
AND WHAT WAS MOST STRIKING IN

5089
04:28:42,566 --> 04:28:46,636
THIS -- AMONG THESE T-CELLS, YOU

5090
04:28:46,636 --> 04:28:53,243
ARE MISSING THE KRG1 -- CELL

5091
04:28:53,243 --> 04:28:58,248
POPULATION, INDICATING THAT NOT

5092
04:28:58,248 --> 04:29:00,350
ABLE TO CLEAR VIRUS, NO EFFECTOR

5093
04:29:00,350 --> 04:29:00,550
CELLS.

5094
04:29:00,550 --> 04:29:02,452
IT ALSO TELLS YOU THE UPR

5095
04:29:02,452 --> 04:29:05,622
CONTRIBUTES TO THIS PROCESS THAT

5096
04:29:05,622 --> 04:29:06,556
GENERATES EFFECTOR CELLS.

5097
04:29:06,556 --> 04:29:10,860
SO THE QUESTION WE WANTED TO GET

5098
04:29:10,860 --> 04:29:13,463
AT, WHAT ARE THEY BECOMING?

5099
04:29:13,463 --> 04:29:18,568
SO TO GET AT THAT, WE PERFORMED

5100
04:29:18,568 --> 04:29:24,274
RNA-SEQ ON T-CELLS FROM THIS ACE

5101
04:29:24,274 --> 04:29:26,343
MODEL AND CONSISTENTLY NOT CLEAG

5102
04:29:26,343 --> 04:29:29,679
VIRUS, THEY LACK A LOT OF THE

5103
04:29:29,679 --> 04:29:33,817
CLASSICAL EFFECTOR PROGRAM.

5104
04:29:33,817 --> 04:29:36,453
WHAT WAS SURPRISING IS WHEN WE

5105
04:29:36,453 --> 04:29:41,057
LOOKED AT THE -- IN CONTRAST TOE

5106
04:29:41,057 --> 04:29:43,159
DEFICIENCY PROGRAM THEY COMPLETY

5107
04:29:43,159 --> 04:29:46,830
EXPRESSED A LARGE SET OF CLASSIL

5108
04:29:46,830 --> 04:29:50,700
T-CELL EXPRESSION MARKERS.

5109
04:29:50,700 --> 04:29:54,938
SO YOUR USUAL SUSPECTS -- THAT S

5110
04:29:54,938 --> 04:29:58,842
ALSO TRUE AT THE PROTEIN LEVEL.

5111
04:29:58,842 --> 04:29:59,676
SO LACT EFFECTOR GENES AND ENZYE

5112
04:29:59,676 --> 04:30:02,846
AND THEY HAVE VERY HIGH LEVELS F

5113
04:30:02,846 --> 04:30:06,249
PD-1 AND TOX 1.

5114
04:30:06,249 --> 04:30:09,552
SO SO FAR, THE UPR MAY NOT BE

5115
04:30:09,552 --> 04:30:10,754
IMPORTANT FOR THE DEVELOPMENT OF

5116
04:30:10,754 --> 04:30:13,490
T-CELLS BUT WE THINK THAT WE FID

5117
04:30:13,490 --> 04:30:16,259
THAT IT IS ESSENTIAL TO GIVE YOU

5118
04:30:16,259 --> 04:30:18,762
EFFECTOR T-CELLS.

5119
04:30:18,762 --> 04:30:20,964
AND JUST IF YOU WERE CURIOUS,

5120
04:30:20,964 --> 04:30:24,367
PHENOTYPE OF THESE T-CELLS ARE

5121
04:30:24,367 --> 04:30:26,069
TERMINAL.

5122
04:30:26,069 --> 04:30:28,772
SO VERY HIGH FOR PD-1.

5123
04:30:28,772 --> 04:30:30,473
SO BECAUSE THIS WAS A VERY

5124
04:30:30,473 --> 04:30:32,375
STRIKING -- WE WANTED TO GET AT

5125
04:30:32,375 --> 04:30:37,681
BASIS OF HOW THIS WAS HAPPENINGD

5126
04:30:37,681 --> 04:30:40,050
ONE -- THE QUESTION WE ASKED, DS

5127
04:30:40,050 --> 04:30:42,786
ANIMAL STILL HAVE VIRUS BECAUSE

5128
04:30:42,786 --> 04:30:44,487
THEY EXPRESS VIRUS THAT WAS TRAD

5129
04:30:44,487 --> 04:30:46,256
IN THE EXOZOME PROGRAM?

5130
04:30:46,256 --> 04:30:48,591
SO WE ENVISION A SCENARIO WHEREE

5131
04:30:48,591 --> 04:30:50,393
CLEAR THE VIRUS, AND PROVIDE THM

5132
04:30:50,393 --> 04:30:52,362
WITH CELLS THAT ARE ABLE TO CLER

5133
04:30:52,362 --> 04:30:57,867
THE VIRUS, ARE THE CELLS ABLE TO

5134
04:30:57,867 --> 04:30:58,968
DIFFERENTIATE INTO EFFECTORS?

5135
04:30:58,968 --> 04:31:05,275
WE DID THAT BY TRANSFERRING P14.

5136
04:31:05,275 --> 04:31:08,378
SO WILDTYPE P14 INTO OUR WILDTYE

5137
04:31:08,378 --> 04:31:10,280
ANIMALS AND KNOCKOUT ANIMALS.

5138
04:31:10,280 --> 04:31:14,918
SO NOW EFFECTOR T-CELLS.

5139
04:31:14,918 --> 04:31:15,785
AS WONG EXPECT, THESE WILDTYPE

5140
04:31:15,785 --> 04:31:19,389
CELLS WE PROVIDED THEM, WHICH IA

5141
04:31:19,389 --> 04:31:22,492
BLUE GRAPH HERE, THEY

5142
04:31:22,492 --> 04:31:23,493
DIFFERENTIATED SIMILARLY ACROSS

5143
04:31:23,493 --> 04:31:25,628
YOUR WILDTYPE AND YOUR KNOCKOUT

5144
04:31:25,628 --> 04:31:25,829
HOST.

5145
04:31:25,829 --> 04:31:27,697
SO IF YOU LOOK AT PD-1 AND TOX ,

5146
04:31:27,697 --> 04:31:29,699
THEY ARE EQUALLY EXPRESSED TO TE

5147
04:31:29,699 --> 04:31:32,268
SAME DEGREE ACROSS THE WILDTYPED

5148
04:31:32,268 --> 04:31:38,241
THE UPR KNOCKOUT HOST.

5149
04:31:38,241 --> 04:31:41,578
WHAT HAPPENS TO THE WILDTYPE CES

5150
04:31:41,578 --> 04:31:43,880
AND THE UPR KNOCKOUT?

5151
04:31:43,880 --> 04:31:48,585
SO IF YOU LOOK AGAIN THE ENDOGES

5152
04:31:48,585 --> 04:31:50,887
CELLS IN BOTH -- EVEN IN THE ANL

5153
04:31:50,887 --> 04:31:53,390
THAT HAS BEEN ABLE TO RESOLVE

5154
04:31:53,390 --> 04:31:55,492
VIRUS, THEY STILL EXPRESS VERY H

5155
04:31:55,492 --> 04:32:00,797
VIRUS OF TOX, SUGGESTING THAT TS

5156
04:32:00,797 --> 04:32:05,969
PROGRAM CONTROLS THE EXHAUSTION

5157
04:32:05,969 --> 04:32:08,505
PHENOTYPE -- SO WHAT DOES THAT L

5158
04:32:08,505 --> 04:32:08,805
US?

5159
04:32:08,805 --> 04:32:13,710
THE SET OF EXPERIMENTS I SHOWEDU

5160
04:32:13,710 --> 04:32:15,111
IS THAT EXHAUSTION IS ASSOCIATEE

5161
04:32:15,111 --> 04:32:18,882
WITH LOW UPR ACTIVITY AND THE

5162
04:32:18,882 --> 04:32:23,052
PROGRAMMED THAT DRIVES THE EFFET

5163
04:32:23,052 --> 04:32:25,288
OF T-CELL GENERATION REQUIRES

5164
04:32:25,288 --> 04:32:31,294
ACTIVATION OF THE PROTEIN RESPO.

5165
04:32:31,294 --> 04:32:34,464
SO IN THE -- ABSENCE OF UPR WILL

5166
04:32:34,464 --> 04:32:36,299
PROMOTE CELLS AND CAUSE THEM TO

5167
04:32:36,299 --> 04:32:39,702
BECOME EXHAUSTED.

5168
04:32:39,702 --> 04:32:43,106
SO THIS WAS GENERALIZABLE TO

5169
04:32:43,106 --> 04:32:46,910
INFECTION MODELS -- LOOK AT THIS

5170
04:32:46,910 --> 04:32:50,914
NOW IN HUMAN AND DATASETS IN HUN

5171
04:32:50,914 --> 04:32:51,181
INFECTION.

5172
04:32:51,181 --> 04:32:56,219
HERE THIS IS DATA FROM OUR HIV.

5173
04:32:56,219 --> 04:33:01,124
SO T-CELLS -- WE LOOKED AT THE

5174
04:33:01,124 --> 04:33:02,492
DIFFERENT CLUSTERS FOCUS ON THE

5175
04:33:02,492 --> 04:33:04,794
CLUSTERS THAT REPRESENT THE

5176
04:33:04,794 --> 04:33:06,696
EXHAUSTED POPULATION AND EFFECTR

5177
04:33:06,696 --> 04:33:07,096
POPULATION.

5178
04:33:07,096 --> 04:33:09,432
I WANT TO JUST POINT OUT HERE TT

5179
04:33:09,432 --> 04:33:12,702
AS WE SEE PREVIOUSLY, THERE IS L

5180
04:33:12,702 --> 04:33:19,309
THE -- FOR UPR PROGRAMS TURN ONN

5181
04:33:19,309 --> 04:33:21,544
EFFECTOR CELLS AND IN THE TEAR,

5182
04:33:21,544 --> 04:33:23,947
EXHAUSTED CLUSTER, THESE PROGRAS

5183
04:33:23,947 --> 04:33:25,248
ARE VERY LIMITED.

5184
04:33:25,248 --> 04:33:27,350
THEY ARE ALMOST ABSENT.

5185
04:33:27,350 --> 04:33:28,952
THIS SUGGESTS THAT THIS MECHANIM

5186
04:33:28,952 --> 04:33:33,957
INVOLVING UPR EXHAUSTION IS

5187
04:33:33,957 --> 04:33:37,260
POTENTIALLY HAPPENING IN ALL

5188
04:33:37,260 --> 04:33:39,529
DISEASE IN NORMAL HUMAN CONTEXT.

5189
04:33:39,529 --> 04:33:42,532
THIS IS ALSO TRUE FOR COVID.

5190
04:33:42,532 --> 04:33:44,734
SO IN MY FINAL FEW MINUTES, I WD

5191
04:33:44,734 --> 04:33:47,370
LIKE TO GET AT THE MECHANISM WHH

5192
04:33:47,370 --> 04:33:49,038
WE THINK THIS IS HAPPENING.

5193
04:33:49,038 --> 04:33:54,043
SO HOW IS THE UPR PROMOTING

5194
04:33:54,043 --> 04:33:54,844
EFFECTOR?

5195
04:33:54,844 --> 04:33:59,282
DIFFERENTIATION AT THE SAME TIME

5196
04:33:59,282 --> 04:33:59,582
EXHAUSTION.

5197
04:33:59,582 --> 04:34:00,216
SO THERE ARE TWO REAL SPECIFIC

5198
04:34:00,216 --> 04:34:01,150
PROBLEMS HERE.

5199
04:34:01,150 --> 04:34:03,152
WHAT IS THE BASIS OF REDUNDANCY?

5200
04:34:03,152 --> 04:34:06,055
THIS IS ACTING REDUNDANCY AND WT

5201
04:34:06,055 --> 04:34:07,957
I DIDN'T MENTION IS THAT THE SAE

5202
04:34:07,957 --> 04:34:12,962
SOURCE OF THE UPR IS SIMILAR

5203
04:34:12,962 --> 04:34:13,696
PROTEINS.

5204
04:34:13,696 --> 04:34:17,066
DOWNSTREAM THEY TURNED ON BASICY

5205
04:34:17,066 --> 04:34:17,734
PROTEINS.

5206
04:34:17,734 --> 04:34:18,535
THEN SECOND QUESTION I DON'T THK

5207
04:34:18,535 --> 04:34:21,638
I'LL HAVE TIME TO GET TO TODAY,

5208
04:34:21,638 --> 04:34:22,872
SPECIFIC EFFECTOR PROGRAM KNOWNS

5209
04:34:22,872 --> 04:34:26,175
UPR TURNING ON, THAT IS DRIVINGE

5210
04:34:26,175 --> 04:34:27,377
EFFECTOR PROGRAM.

5211
04:34:27,377 --> 04:34:32,916
SO, THE FIRST QUESTION WAS, WHAS

5212
04:34:32,916 --> 04:34:35,451
THE BASIS OF THIS REDUNDANCY?

5213
04:34:35,451 --> 04:34:40,156
SO DOWNSTREAM OF THESE ENZYMES E

5214
04:34:40,156 --> 04:34:43,660
BASICALLY TRANSCRIPTION FACTORSD

5215
04:34:43,660 --> 04:34:46,763
WE HAVE THESE PROTEINS MAY FUNCN

5216
04:34:46,763 --> 04:34:48,064
REDUNDANTLY AND INTERCHANGEABLY

5217
04:34:48,064 --> 04:34:51,701
SUCH THAT WHEN ONE ENZYME IS

5218
04:34:51,701 --> 04:34:54,771
MISSING, CAN BUFFER THE PROGRAM.

5219
04:34:54,771 --> 04:34:58,074
SO TO TEST THAT, WE TOOK THE UPR

5220
04:34:58,074 --> 04:35:01,578
KNOCKOUT ANIMAL AND

5221
04:35:01,578 --> 04:35:02,579
TRANSGENERICALLY INTRODUCED IN A

5222
04:35:02,579 --> 04:35:09,352
CONDITIONAL MANNER THE -- TURNED

5223
04:35:09,352 --> 04:35:10,720
ON.

5224
04:35:10,720 --> 04:35:11,688
THIS ANIMAL LACKED THREE SENSORS

5225
04:35:11,688 --> 04:35:14,857
AND ONLY EXPRESSED JUST THIS

5226
04:35:14,857 --> 04:35:16,259
DOWNSTREAM -- SO THE QUESTION WE

5227
04:35:16,259 --> 04:35:18,094
ASKED WAS WHAT HAPPENS WHEN WE

5228
04:35:18,094 --> 04:35:23,866
INFECT THESE ANIMALS AND SBP1 WE

5229
04:35:23,866 --> 04:35:26,903
PUT BACK IN SUFFICIENT TO RESTOE

5230
04:35:26,903 --> 04:35:29,372
NOW THE -- SO I'M SHOWING HERE

5231
04:35:29,372 --> 04:35:32,775
CLASSIC DATA JUST TO GIVE A MORE

5232
04:35:32,775 --> 04:35:35,278
DEPTH INTO WHAT WE FOUND.

5233
04:35:35,278 --> 04:35:38,982
SO IN OUR KNOCKOUT AT DAY 8, INE

5234
04:35:38,982 --> 04:35:42,885
ABSENCE OF UPR YOU SEE MASSIVE

5235
04:35:42,885 --> 04:35:46,789
CHANGES IN THE LANDSCAPE SHOWING

5236
04:35:46,789 --> 04:35:47,890
HERE BY THIS.

5237
04:35:47,890 --> 04:35:56,899
WHEN WE INTRODUCED OUR XBP1, WE

5238
04:35:56,899 --> 04:36:00,903
LARGELY -- RESCUED -- MORE

5239
04:36:00,903 --> 04:36:04,874
IMPORTANTLY, KNOCKOUT WE DON'T

5240
04:36:04,874 --> 04:36:06,309
GENERATE EFFECTOR CELLS.

5241
04:36:06,309 --> 04:36:12,148
BUT WHEN WE PUT BACK XBP1, YOU E

5242
04:36:12,148 --> 04:36:14,083
THAT WE ALSO ARE RESTORE THE

5243
04:36:14,083 --> 04:36:16,352
NUMBERS OF EFFECTOR T-CELL

5244
04:36:16,352 --> 04:36:16,653
POPULATION.

5245
04:36:16,653 --> 04:36:21,858
AND THOSE EFFECTOR T-CELLS NOW E

5246
04:36:21,858 --> 04:36:24,794
LAUER LEVELS OF PD-1 AND TOX.

5247
04:36:24,794 --> 04:36:27,697
SO IN CONCLUSION WHAT I HAVE SHN

5248
04:36:27,697 --> 04:36:30,299
YOU TODAY, WE THINK THAT UPR PLS

5249
04:36:30,299 --> 04:36:33,369
IMPORTANT ROLE IN EFFECTOR T-CEL

5250
04:36:33,369 --> 04:36:34,704
DIFFERENTIATION AND THE UPR MAYE

5251
04:36:34,704 --> 04:36:38,808
A MECHANISM TO PREVENT THIS

5252
04:36:38,808 --> 04:36:39,809
EXHAUSTION OF T-CELL PROGRAM.

5253
04:36:39,809 --> 04:36:41,077
I DON'T KNOW IF I HAVE TIME BUTI

5254
04:36:41,077 --> 04:36:42,412
WILL PROBABLY END IT HERE.

5255
04:36:42,412 --> 04:36:46,115
WE NOW HAVE A CLUE -- MORE INSIT

5256
04:36:46,115 --> 04:36:47,684
IN SOME OF THESE DOWNSTREAM WHAM

5257
04:36:47,684 --> 04:36:49,285
AND ONE OF THE WAYS THAT LOOKEDT

5258
04:36:49,285 --> 04:36:54,891
THE DEPENDENT ON THE SIGNALING S

5259
04:36:54,891 --> 04:36:57,093
THE -- SUCH THAT WHEN THERE IS O

5260
04:36:57,093 --> 04:37:00,196
UPR, YOU DISRUPT OR DOWN REGULAE

5261
04:37:00,196 --> 04:37:02,098
ID2 PROGRAM.

5262
04:37:02,098 --> 04:37:05,301
THAT IS INTERESTING BECAUSE WORY

5263
04:37:05,301 --> 04:37:08,938
OTHERS YEARS AGO SHOWED THAT ADD

5264
04:37:08,938 --> 04:37:11,207
TO ANIMALS -- EFFECTOR CELLS SO

5265
04:37:11,207 --> 04:37:13,309
CONSISTENT WITH WHAT WE FIND.

5266
04:37:13,309 --> 04:37:20,116
AND THEN WE ALSO HAVE -- I'M NOT

5267
04:37:20,116 --> 04:37:21,017
GOING TO GO INTO THAT.

5268
04:37:21,017 --> 04:37:23,519
I'M GOING TO STOP HERE AND TAKEY

5269
04:37:23,519 --> 04:37:23,786
QUESTIONS.

5270
04:37:23,786 --> 04:37:33,996
[ APPLAUSE ]

5271
04:37:35,198 --> 04:37:35,832
>> THANK YOU.

5272
04:37:35,832 --> 04:37:38,034
I GUESS MAYBE YOUR LAST POINT

5273
04:37:38,034 --> 04:37:41,003
ADDRESSED THIS SOMEWHAT BUT I'M

5274
04:37:41,003 --> 04:37:42,538
WONDERING WHETHER THE EXHAUSTIOS

5275
04:37:42,538 --> 04:37:44,140
AN INDIRECT CONSEQUENCE OF JUSTA

5276
04:37:44,140 --> 04:37:45,875
REALLY STRONG HIT THAT THEY'RE

5277
04:37:45,875 --> 04:37:48,411
GETTING OR ARE THEY COMPLETELY Y

5278
04:37:48,411 --> 04:37:51,647
PASSING THE EFFECTOR STAGE AND

5279
04:37:51,647 --> 04:37:52,415
GOING STRAIGHT TO EXHAUSTION?

5280
04:37:52,415 --> 04:37:55,818
>> SO GREAT QUESTION.

5281
04:37:55,818 --> 04:37:57,487
SO WE LOOKED HARD AND NOT SEEN Y

5282
04:37:57,487 --> 04:38:01,124
OF THE -- IT LOOKS LIKE REALLY

5283
04:38:01,124 --> 04:38:01,924
BYPASSING.

5284
04:38:01,924 --> 04:38:03,726
WE DON'T SEE ENOUGH OF THE -- AS

5285
04:38:03,726 --> 04:38:09,532
EARLY AS DAY 3 WE SEE THIS VERYW

5286
04:38:09,532 --> 04:38:09,932
KLGR1 LOAD.

5287
04:38:09,932 --> 04:38:11,834
SO IT LOOKS LIKE THEY ARE BYPASG

5288
04:38:11,834 --> 04:38:12,368
THAT STAGE.

5289
04:38:12,368 --> 04:38:18,141
SO THAT IS PROBABLY WHAT I WOULD

5290
04:38:18,141 --> 04:38:19,075
SAY.

5291
04:38:19,075 --> 04:38:24,981
>> CLARIFY -- ARMSTRONG --

5292
04:38:24,981 --> 04:38:28,251
[ LOW AUDIO ]

5293
04:38:28,251 --> 04:38:29,152
>> THAT'S THE EXPERIMENT
WE ARE

5294
04:38:29,152 --> 04:38:30,219
SETTING UP TO DO NOW.

5295
04:38:30,219 --> 04:38:32,255
THE QUESTION IS WHETHER WE CAN

5296
04:38:32,255 --> 04:38:35,958
NOW -- CAN WE REVERT OR RESCUE

5297
04:38:35,958 --> 04:38:38,961
EXHAUSTION IN OUR MODEL?

5298
04:38:38,961 --> 04:38:40,830
WE ARE LOOKING AT THAT NOW.

5299
04:38:40,830 --> 04:38:43,132
GOOD QUESTION.

5300
04:38:43,132 --> 04:38:43,833
>> GREAT TALK.

5301
04:38:43,833 --> 04:38:50,640
SO EFFECTOR CD8S SHOW A HIGH UPR

5302
04:38:50,640 --> 04:38:51,374
SIGNATURE.

5303
04:38:51,374 --> 04:38:53,242
WHY -- CAN YOU SPECULATE ON WHYU

5304
04:38:53,242 --> 04:38:58,681
THINK WHY IT'S SO SYNTHETIC FOR

5305
04:38:58,681 --> 04:39:01,551
GRANULES AND INTERFERON GAMMA?

5306
04:39:01,551 --> 04:39:03,653
IT'S INTERESTING BECAUSE IT KINF

5307
04:39:03,653 --> 04:39:05,454
PARALLELS A PLASMA CELL BUT NOT

5308
04:39:05,454 --> 04:39:08,357
QUITE AS DRAMATIC.

5309
04:39:08,357 --> 04:39:12,261
>> THAT'S A VERY
INTERESTING

5310
04:39:12,261 --> 04:39:12,562
QUESTION.

5311
04:39:12,562 --> 04:39:16,265
ALSO WHY HAS THE SYSTEM EVOLVED

5312
04:39:16,265 --> 04:39:21,070
TO -- UPR INTO A PROGRAM -- INTO

5313
04:39:21,070 --> 04:39:22,238
THE EFFECTOR CELL PROGRAM?

5314
04:39:22,238 --> 04:39:26,976
ON THE ONE HAND, YOU ARE CORRECT

5315
04:39:26,976 --> 04:39:31,881
THAT THE ACTIVATED CD8 T-CELLS E

5316
04:39:31,881 --> 04:39:34,283
EXPANDING TO MAKE MORE CYTOKINEO

5317
04:39:34,283 --> 04:39:35,318
MAKE EFFECTORS.

5318
04:39:35,318 --> 04:39:42,692
BUT IT TURNS OUT THAT IN THE

5319
04:39:42,692 --> 04:39:45,194
ABSENCE OF THE -- WE HAVE TRIEDO

5320
04:39:45,194 --> 04:39:51,400
RESCUE THESE ANIMALS -- ONE

5321
04:39:51,400 --> 04:39:55,972
POSSIBLY IF WE GIVE THEM CHEMICL

5322
04:39:55,972 --> 04:40:06,549
CHAPERONES THAT CAN RESTORE THET

5323
04:40:07,483 --> 04:40:10,419
IS TRUE THIS PATHWAY IS POTENTIL

5324
04:40:10,419 --> 04:40:13,222
TOW HELP PROTEIN SYNTHESIS OR

5325
04:40:13,222 --> 04:40:19,428
T-CELLS: BUT THE FACTORS ARE ALO

5326
04:40:19,428 --> 04:40:21,297
SOMEHOW COUPLED TO THE -- WHICH

5327
04:40:21,297 --> 04:40:25,735
COULD BE POTENTIALLY TO --

5328
04:40:25,735 --> 04:40:30,239
CHECKPOINT TO ENSURE THAT THE CS

5329
04:40:30,239 --> 04:40:35,244
ARE PREPARED -- MAKING EFFECTOR-

5330
04:40:35,244 --> 04:40:42,551
ALSO BETTER ABLE TO --

5331
04:40:42,551 --> 04:40:46,522
>> SO THANK YOU.

5332
04:40:46,522 --> 04:40:50,226
SO WHEN P14 TRANSGENIC EXPERIME,

5333
04:40:50,226 --> 04:40:53,829
THE CELLS YOU TRANSFERRED WERE L

5334
04:40:53,829 --> 04:40:54,163
WILDTYPE.

5335
04:40:54,163 --> 04:40:59,268
YOU DIDN'T TRANSFER THE CURE CES

5336
04:40:59,268 --> 04:41:00,469
INTO WILDTYPE MOUSE.

5337
04:41:00,469 --> 04:41:01,370
>> SIGH THAT AGAIN.

5338
04:41:01,370 --> 04:41:04,440
>> DID YOU TRANSFER P14
KNOCKOUT

5339
04:41:04,440 --> 04:41:05,541
INTO WILDTYPE MICE?

5340
04:41:05,541 --> 04:41:07,043
>> WE HAVE DONE THAT AS
WELL.

5341
04:41:07,043 --> 04:41:08,945
WE HAVE DONE TWO MODELS WHERE WE

5342
04:41:08,945 --> 04:41:13,049
HAVE THE P14 KNOCKOUT INTO THE E

5343
04:41:13,049 --> 04:41:13,349
HOST.

5344
04:41:13,349 --> 04:41:16,052
YOU ALSO FIND THAT THE KNOCKOUT

5345
04:41:16,052 --> 04:41:18,321
CELLS DON'T MAKE EFFECTOR CELL.

5346
04:41:18,321 --> 04:41:19,555
>> EVEN IN WILDTYPE HOST?

5347
04:41:19,555 --> 04:41:20,856
>> EVEN IN WILDTYPE HOST.

5348
04:41:20,856 --> 04:41:24,660
>> SO YOU HAVE INDEED --

5349
04:41:24,660 --> 04:41:27,163
>> EVEN IN WILDTYPE HOST
THEY DT

5350
04:41:27,163 --> 04:41:27,863
MAKE -- YES.

5351
04:41:27,863 --> 04:41:28,864
>> THANK YOU.

5352
04:41:28,864 --> 04:41:31,334
>> NICE TALK, I'M CURIOUS
ABOUTE

5353
04:41:31,334 --> 04:41:34,370
HIV DATASET YOU SHOWED.

5354
04:41:34,370 --> 04:41:35,671
WERE THE PATIENTS ON THERAPY AND

5355
04:41:35,671 --> 04:41:39,375
WAS THIS FROM A CHRONIC INFECTIN

5356
04:41:39,375 --> 04:41:40,343
TIME POINT?

5357
04:41:40,343 --> 04:41:44,246
>> SO THE PATIENTS ARE --
YES,

5358
04:41:44,246 --> 04:41:44,780
PATIENTS WERE ON THERAPY.

5359
04:41:44,780 --> 04:41:51,354
THIS WAS IS PUBLISHED -- I'M SO,

5360
04:41:51,354 --> 04:41:55,024
YES THEY WERE ON SOME THERAPY.

5361
04:41:55,024 --> 04:41:57,960
[ INAUDIBLE ]

5362
04:41:57,960 --> 04:41:59,662
>> SO THESE ARE QUESTIONS
-- IT

5363
04:41:59,662 --> 04:42:00,463
WASN'T CLARIFIED.

5364
04:42:00,463 --> 04:42:02,665
IT WAS NOT DATA FROM US BUT IT

5365
04:42:02,665 --> 04:42:05,167
WASN'T CLARIFIED IN THAT DATASET

5366
04:42:05,167 --> 04:42:08,170
BUT -- I MEAN, THE REASON I WAS

5367
04:42:08,170 --> 04:42:11,974
SHOWING IS TO AVOID THE FACT THT

5368
04:42:11,974 --> 04:42:13,609
WITHIN THE PROCESS AFFECTED BY V

5369
04:42:13,609 --> 04:42:18,547
AND THAT POTENTIALLY IMPACT THE 

5370
04:42:18,547 --> 04:42:18,714
UPR.

5371
04:42:18,714 --> 04:42:23,586
SO THAT WAS FOCUSED ON THE CD8

5372
04:42:23,586 --> 04:42:23,886
POPULATION.

5373
04:42:23,886 --> 04:42:25,688
>> THANK YOU VERY MUCH.

5374
04:42:25,688 --> 04:42:26,455
FASCINATING TALK.

5375
04:42:26,455 --> 04:42:36,665
[ APPLAUSE ]

5376
04:42:51,981 --> 04:42:53,182
>> IT IS MY PLEASURE TO
ANNOUNCE

5377
04:42:53,182 --> 04:42:55,084
THE LAST SPEAKER OF THIS SESSIO,

5378
04:42:55,084 --> 04:43:01,857
WHICH IS SHORTENED.

5379
04:43:01,857 --> 04:43:05,094
THIS IS JAGAN MUPPIDI WHO WILL L

5380
04:43:05,094 --> 04:43:07,263
US ABOUT NUTRIENT DRIVEN

5381
04:43:07,263 --> 04:43:11,067
PROLIFERATION IN MUCOSAL GERMINL

5382
04:43:11,067 --> 04:43:11,300
CENTERS.

5383
04:43:11,300 --> 04:43:15,071
>> CAN YOU HEAR ME?

5384
04:43:15,071 --> 04:43:16,672
SO, CHRISTIAN ALREADY DID A NICE

5385
04:43:16,672 --> 04:43:19,742
JOB OF INTRODUCING THE GERMINAL

5386
04:43:19,742 --> 04:43:21,677
CERTAINLY BUT THE ONGOING

5387
04:43:21,677 --> 04:43:22,878
MUTATIONAL PROGRAM THAT LEADS TO

5388
04:43:22,878 --> 04:43:24,980
HIGH AFFINITY ANTIBODIES CAN ALO

5389
04:43:24,980 --> 04:43:29,785
GENERATE MUTATIONS THAT CAN LEAO

5390
04:43:29,785 --> 04:43:31,887
GENERATION OF MALIGNANCIES.

5391
04:43:31,887 --> 04:43:34,290
I'M INTERESTED IN TWO AGGRESSIVE

5392
04:43:34,290 --> 04:43:38,894
MALIGNANCIES THAT ARE DERIVED FM

5393
04:43:38,894 --> 04:43:40,896
GERMINAL CENTER B CELLS, LYMPHOA

5394
04:43:40,896 --> 04:43:44,500
AND BURKITT'S LYMPHOMA.

5395
04:43:44,500 --> 04:43:45,367
SO THE GERMINAL CENTERS DIVIDED

5396
04:43:45,367 --> 04:43:47,002
INTO TWO ZONES.

5397
04:43:47,002 --> 04:43:50,306
IN THE LIGHT ZONE SELECTED EVENS

5398
04:43:50,306 --> 04:43:53,075
HAPPEN THAT ARE T-CELL MEDIATED

5399
04:43:53,075 --> 04:43:57,580
WHEREAS IN THE DARK ZONE SOMATIC

5400
04:43:57,580 --> 04:43:58,247
HYPERMEITATION.

5401
04:43:58,247 --> 04:44:00,282
AND THE INITIAL SELECTION OF RAE

5402
04:44:00,282 --> 04:44:02,785
CLONES IN THE LIGHT ZONE IS

5403
04:44:02,785 --> 04:44:05,154
MEDIATED PRIMARILY BY T-CELL HEP

5404
04:44:05,154 --> 04:44:07,590
WHICH LEADS TO INCREASE mTOR 1

5405
04:44:07,590 --> 04:44:11,260
SIGNALING AND INCREASED MYC

5406
04:44:11,260 --> 04:44:15,030
ABUNDANCE INSIDE

5407
04:44:15,030 --> 04:44:16,499
POSITIVELY-SELECTED CELLS.

5408
04:44:16,499 --> 04:44:19,235
SO THE BALANCE BETWEEN LIGHT ZOE

5409
04:44:19,235 --> 04:44:22,805
AND TACKER ZONE IS MEDIATED BY E

5410
04:44:22,805 --> 04:44:26,208
DIFFERENCES IN THE ABUNDANCE OF

5411
04:44:26,208 --> 04:44:28,410
ACTIVE ADA AND FOX O1.

5412
04:44:28,410 --> 04:44:31,313
SO INCREASED FOX FORELATED AKT

5413
04:44:31,313 --> 04:44:34,984
WHICH LEADS TO PHOSPHORYLATION D

5414
04:44:34,984 --> 04:44:36,285
DEGRADATION OF FOX O1 AND IN THE

5415
04:44:36,285 --> 04:44:39,488
DARK ZONE IT IS THOUGHT THAT IS

5416
04:44:39,488 --> 04:44:40,823
REVERSED AND IT ALLOWS THE DARK

5417
04:44:40,823 --> 04:44:47,463
ZONE PROGRAMS TO TAKE PLACE.

5418
04:44:47,463 --> 04:44:48,297
SO, GERMINAL CENTERS FORM AT THE

5419
04:44:48,297 --> 04:44:54,937
CENTER OF THE B-CELL FOLLICLE AD

5420
04:44:54,937 --> 04:44:56,906
THIS CONFINEMENT TO THE GC NISHS

5421
04:44:56,906 --> 04:44:59,608
MEDIATED PRIMARILY BY TWO PROTEN

5422
04:44:59,608 --> 04:45:02,111
COUPLED RECEPTORS, WHICH ACT

5423
04:45:02,111 --> 04:45:05,614
THROUGH THE G PROTEIN G ALPHA 1O

5424
04:45:05,614 --> 04:45:07,550
INHIBIT MIGRATION.

5425
04:45:07,550 --> 04:45:08,684
SO THAT CONFINEMENT OCCURS IN TE

5426
04:45:08,684 --> 04:45:12,121
CONTEXT OF A DECAYING GRADIENT F

5427
04:45:12,121 --> 04:45:13,122
THE LIGANDS FOR THESE TWO

5428
04:45:13,122 --> 04:45:13,789
RECEPTORS.

5429
04:45:13,789 --> 04:45:16,525
SO, IN THE ABSENCE OF G ALPHA 1E

5430
04:45:16,525 --> 04:45:18,127
SHOWED A NUMBER OF YEARS AGO THT

5431
04:45:18,127 --> 04:45:20,429
YOU CAN SEE SPREAD OF I CAN'T

5432
04:45:20,429 --> 04:45:21,130
REMEMBERINAL CENTER B CELLS

5433
04:45:21,130 --> 04:45:22,431
THROUGHOUT THE FOLLICLE AND YOUN

5434
04:45:22,431 --> 04:45:26,902
FIND THEM IN CIRCULATION WHEREAS

5435
04:45:26,902 --> 04:45:29,939
NORMAL GERMINAL B CELLS ARE NON

5436
04:45:29,939 --> 04:45:30,272
RECIRCULATORY.

5437
04:45:30,272 --> 04:45:32,041
AND WE WERE PARTICULARLY INTERED

5438
04:45:32,041 --> 04:45:34,343
IN THIS PATHWAY BECAUSE MUTATIOS

5439
04:45:34,343 --> 04:45:38,247
IN EITHER THE RECEPTORS OR G ALA

5440
04:45:38,247 --> 04:45:41,217
13 ARE AMONG THE MOST COMMON

5441
04:45:41,217 --> 04:45:44,753
GENETIC EVENTS THAT OCCUR IN BOH

5442
04:45:44,753 --> 04:45:48,524
GCB AND B-CELL LYMPHOMA AND BURT

5443
04:45:48,524 --> 04:45:48,791
LYMPHOMA.

5444
04:45:48,791 --> 04:45:51,327
WHEN YOU LOOK AT ANIMALS THAT LK

5445
04:45:51,327 --> 04:45:53,929
G ALPHA 13 IN MATURE B CELLS, YU

5446
04:45:53,929 --> 04:45:58,133
CAN SEE THAT AS WE AGE THESE

5447
04:45:58,133 --> 04:46:02,238
ANIMALS, THEY DEVELOP TUMORS THT

5448
04:46:02,238 --> 04:46:03,639
INTERESTINGLY FORM IN THE -- YOU

5449
04:46:03,639 --> 04:46:07,343
CAN SEE HERE THAT OVER TIME ALLE

5450
04:46:07,343 --> 04:46:09,345
ANIMALS DEVELOP TUMORS THAT LACG

5451
04:46:09,345 --> 04:46:10,279
ALPHA 13.

5452
04:46:10,279 --> 04:46:13,449
IF WE LOOK AT THE DISTRIBUTION F

5453
04:46:13,449 --> 04:46:15,251
TUMORS, THE VAST MAJORITY OF MIE

5454
04:46:15,251 --> 04:46:19,755
THAT HAVE TUMORS HAVE MESS ENTEC

5455
04:46:19,755 --> 04:46:20,856
LYMPH NODE INVOLVEMENT SUGGESTIG

5456
04:46:20,856 --> 04:46:22,458
THAT IS THE SITE OF ORIGIN.

5457
04:46:22,458 --> 04:46:24,827
WHEN WE LOOK AT YOUNGER MICE AND

5458
04:46:24,827 --> 04:46:27,830
MIXED BONE MARROW CAME ERAS WHEE

5459
04:46:27,830 --> 04:46:30,866
WE GENERATED USING G ALPHA 13

5460
04:46:30,866 --> 04:46:33,636
DEFICIENT BONE MARROW MARKED WIH

5461
04:46:33,636 --> 04:46:36,538
CD45.2, THERE IS A VERY STRONG L

5462
04:46:36,538 --> 04:46:38,807
INTRINSIC OUTGROWTH THAT HAPPENN

5463
04:46:38,807 --> 04:46:40,809
THE GERMINAL CERTAINTIES IN MESS

5464
04:46:40,809 --> 04:46:44,046
ENTERIC LYMPH NODES BUT THERE IS

5465
04:46:44,046 --> 04:46:46,649
BASICALLY NO OUT GROWTH THAT

5466
04:46:46,649 --> 04:46:50,953
HAPPENS IN THE BLOOD CELL IMMUND

5467
04:46:50,953 --> 04:46:51,287
SETTINGS.

5468
04:46:51,287 --> 04:46:52,655
SO WE WERE INTERESTED IN TRYINGO

5469
04:46:52,655 --> 04:46:55,557
EVALUATE THE BASIS OF THIS.

5470
04:46:55,557 --> 04:46:59,161
SO, WHEN WE ORIGINALLY WERE LOOG

5471
04:46:59,161 --> 04:47:03,232
AT THESE MICE WE PROPOSED THAT S

5472
04:47:03,232 --> 04:47:07,469
OUTGROWTH AND PROPENSITY TO DEVP

5473
04:47:07,469 --> 04:47:10,072
TUMORS WAS DRIVEN BY INCREASED T

5474
04:47:10,072 --> 04:47:12,441
BECAUSE WHEN WE LOOKED AT SIGNAG

5475
04:47:12,441 --> 04:47:15,944
IN CELLS DIRECTLY EX-VIVO, WE FD

5476
04:47:15,944 --> 04:47:18,247
THE STIMULATION COULD INHIBIT A.

5477
04:47:18,247 --> 04:47:19,848
TO THE WASN'T CLEAR BASED ON THE

5478
04:47:19,848 --> 04:47:20,849
INITIAL STUDIES WHETHER OR NOT T

5479
04:47:20,849 --> 04:47:22,851
WAS THE PRIMARY MECHANISM THAT D

5480
04:47:22,851 --> 04:47:25,688
TO TUMOR FORMATION.

5481
04:47:25,688 --> 04:47:27,456
AND SO, IN DATA THEY DON'T HAVE

5482
04:47:27,456 --> 04:47:30,392
TIME TO SHOW YOU, WE COMPARED

5483
04:47:30,392 --> 04:47:32,261
ANIMALS IN WHICH B CELLS EXPRESS

5484
04:47:32,261 --> 04:47:35,864
HIGHER LEVELS OF AKT.

5485
04:47:35,864 --> 04:47:38,334
AND WHAT WE KNOW FROM PREVIOUS K

5486
04:47:38,334 --> 04:47:40,469
IS THAT IN THOSE SITUATIONS, YOU

5487
04:47:40,469 --> 04:47:41,970
HAVE A BIAS TOWARDS THE LIGHT ZE

5488
04:47:41,970 --> 04:47:45,474
AND RESULTING DECREASE IN

5489
04:47:45,474 --> 04:47:46,075
PROLIFERATION IN THE GERMINAL

5490
04:47:46,075 --> 04:47:46,308
CENTER.

5491
04:47:46,308 --> 04:47:48,077
BUT, IN CONTRAST, IN THE ABSENCF

5492
04:47:48,077 --> 04:47:50,546
G ALPHA 13, WE DIDN'T SEE ANY

5493
04:47:50,546 --> 04:47:52,881
CHANGE IN THE LIGHT ZONE-DARK ZE

5494
04:47:52,881 --> 04:47:53,215
DISTRIBUTION.

5495
04:47:53,215 --> 04:47:54,983
INSTEAD WHAT WE FOUND IS THERE S

5496
04:47:54,983 --> 04:47:55,751
INCREASED PROLIFERATION.

5497
04:47:55,751 --> 04:47:59,555
SO TO TRY TO ADDRESS WHAT THE OR

5498
04:47:59,555 --> 04:48:02,324
MECHANISMS WERE THAT WERE PROMOG

5499
04:48:02,324 --> 04:48:04,093
TUMORIGENESIS IN THE MESS ENTERC

5500
04:48:04,093 --> 04:48:05,361
LYMPH NODE, WE PERFORMED A SINGE

5501
04:48:05,361 --> 04:48:08,464
CELL LINE OF SEQUENCING EXPERIMT

5502
04:48:08,464 --> 04:48:11,400
AND SO WE SORTED GERMINAL CENTEB

5503
04:48:11,400 --> 04:48:13,769
CELLS FROM WILDTYPE AND KNOCKOUT

5504
04:48:13,769 --> 04:48:15,571
ANIMALS FROM POLICE OFFICER LYMH

5505
04:48:15,571 --> 04:48:19,341
NODE THAT HAD BEEN IMMUNIZED FOR

5506
04:48:19,341 --> 04:48:19,975
MESS ENTERIC LYMPH NODE.

5507
04:48:19,975 --> 04:48:21,877
LIGHT ZONE AND DARK ZONE CLUSTES

5508
04:48:21,877 --> 04:48:26,915
ARE HIGHLIGHTED HERE AND THE MES

5509
04:48:26,915 --> 04:48:28,083
ENTERIC LYMPH NODE FROM OUR

5510
04:48:28,083 --> 04:48:31,687
KNOCKOUT ANIMALS, ENRICHMENT IN

5511
04:48:31,687 --> 04:48:33,389
THREE CLUSTERS THAT WERE OUTSIDF

5512
04:48:33,389 --> 04:48:34,890
THE LIGHT ZONE AND DARK ZONE.

5513
04:48:34,890 --> 04:48:37,292
WHEN WE LOOKED AT GENE SIGNATURS

5514
04:48:37,292 --> 04:48:38,794
ENRICHED IN EACH OF THESE CLUST,

5515
04:48:38,794 --> 04:48:42,297
WHAT WE FOUND WAS THAT THERE WAS

5516
04:48:42,297 --> 04:48:45,501
STRIKING  INCREASE IN MULTIPLE

5517
04:48:45,501 --> 04:48:48,737
SIGNATURES OF POSITIVE SELECTION

5518
04:48:48,737 --> 04:48:52,708
INCLUDING MYC AS WELL AS mTOR 1.

5519
04:48:52,708 --> 04:48:55,310
SO, TO VALIDATE THESE GENE

5520
04:48:55,310 --> 04:49:02,885
EXPRESSION SIGNATURES, WE STAIND

5521
04:49:02,885 --> 04:49:05,387
MYC CHIMERA FOR MYC AND THE LIGT

5522
04:49:05,387 --> 04:49:06,188
ZONE GERMINAL CENTER B CELLS, TE

5523
04:49:06,188 --> 04:49:11,026
IS INCREASED ABUNDANCE OF MYC

5524
04:49:11,026 --> 04:49:11,727
PROTEIN IN THE KNOCKOUTS FROM OG

5525
04:49:11,727 --> 04:49:13,996
ALPHA 13 DEFICIENT CELLS.

5526
04:49:13,996 --> 04:49:16,698
AND YOU CAN SEE THAT OVER A NUMR

5527
04:49:16,698 --> 04:49:17,299
OF MICE HERE.

5528
04:49:17,299 --> 04:49:20,135
BUT THERE IS NO CHANGE IN THE

5529
04:49:20,135 --> 04:49:21,837
ABUNDANCE OF MYC IN THE POLICE

5530
04:49:21,837 --> 04:49:22,704
OFFICER LYMPH NODES SUGGESTING S

5531
04:49:22,704 --> 04:49:25,407
IS A SPECIFIC PHENOMENA HAPPENIG

5532
04:49:25,407 --> 04:49:27,009
IN THE SITE WHERE THE MICE GET L

5533
04:49:27,009 --> 04:49:28,811
THE TUMORS.

5534
04:49:28,811 --> 04:49:31,213
SO, TO GET AT A A LITTLE BIT MOE

5535
04:49:31,213 --> 04:49:32,815
MECHANISTICALLY OF WHAT THE

5536
04:49:32,815 --> 04:49:36,618
MECHANISM IS THAT IS LEADING TO

5537
04:49:36,618 --> 04:49:37,619
INCREASED MYC IN THE ABSENCE OFG

5538
04:49:37,619 --> 04:49:39,621
ALPHA 13, WE DEVELOPED A CELL LE

5539
04:49:39,621 --> 04:49:41,123
MODEL I'M NOT GOING TO GET INTOE

5540
04:49:41,123 --> 04:49:43,625
SPECIFIC DETAILS BUT SUFFICE ITO

5541
04:49:43,625 --> 04:49:46,728
SAY, WE PUT IN A RECEPTOR THAT S

5542
04:49:46,728 --> 04:49:50,732
NOT NORMALLY EXPRESSED IN OUR

5543
04:49:50,732 --> 04:49:53,335
GERMINAL CENTER CELL LINE AND WE

5544
04:49:53,335 --> 04:49:54,503
CAN ADD A LIGAND.

5545
04:49:54,503 --> 04:49:56,104
AND WHEN YOU DO THAT, OVER TIME

5546
04:49:56,104 --> 04:49:59,007
THERE IS A DROPOUT OF TRANSDUCED

5547
04:49:59,007 --> 04:50:01,009
CELLS WHEN LIGAND IS ADDED AND E

5548
04:50:01,009 --> 04:50:05,247
CAN SEE THAT THERE IS A STRONG S

5549
04:50:05,247 --> 04:50:08,617
OF MYC AND THEN WHEN WE KNOCKOUG

5550
04:50:08,617 --> 04:50:12,621
ALPHA 13 WITH CRISPR/CAS 9 YOU

5551
04:50:12,621 --> 04:50:14,323
CAN'T SEE A REDUCTION IN MYC.

5552
04:50:14,323 --> 04:50:17,092
SO TO SUMMARIZE SOME DISK WORK I

5553
04:50:17,092 --> 04:50:18,627
DON'T HAVE TIME TO SHOW YOU, WE

5554
04:50:18,627 --> 04:50:20,062
CAME TO THE CONCLUSION THE PRIMY

5555
04:50:20,062 --> 04:50:22,130
REASON WHY THERE WAS A DRAMATIC

5556
04:50:22,130 --> 04:50:26,134
LOSS IN MYC WAS DUE TO DECREASED

5557
04:50:26,134 --> 04:50:26,635
TRANSLATION OF MYC.

5558
04:50:26,635 --> 04:50:28,837
AND THAT DECREASED TRANSLATION S

5559
04:50:28,837 --> 04:50:31,440
DUE TO IN ADDITION OF mTOR 1.

5560
04:50:31,440 --> 04:50:37,045
SO WHEN WE DID OUR MIXED CULTURE

5561
04:50:37,045 --> 04:50:39,047
EXPERIMENT WHERE WE FOUND IF WE

5562
04:50:39,047 --> 04:50:41,550
TREATED THESE CELLS WITH RAPAMYN

5563
04:50:41,550 --> 04:50:44,520
TO INHIBIT mTOR 1, IN THE

5564
04:50:44,520 --> 04:50:46,655
PRESENCE OF STIMULATION OF G ALA

5565
04:50:46,655 --> 04:50:50,225
13, OUR KNOCKOUT CELLS CAN OUT W

5566
04:50:50,225 --> 04:50:51,527
WILDTYPE COMPETITORS ROBUSTLY AD

5567
04:50:51,527 --> 04:50:54,229
THAT IS DECREASED IN THE PRESENE

5568
04:50:54,229 --> 04:50:57,799
OF mTOR 1 INHIBITION SUGGESTING

5569
04:50:57,799 --> 04:50:59,034
EXAGGERATED mTOR ONE IS

5570
04:50:59,034 --> 04:51:01,036
RESPONSIBLE, IN PART, FOR THE

5571
04:51:01,036 --> 04:51:01,737
OPERATIVE IN VITRO.

5572
04:51:01,737 --> 04:51:06,542
WHEN WE LOOKED AT MYC BONE MARRW

5573
04:51:06,542 --> 04:51:08,944
CHIMERA THAT HAS BEEN TREATED WH

5574
04:51:08,944 --> 04:51:09,745
RAPAMYCIN, THERE WAS DECREASE IN

5575
04:51:09,745 --> 04:51:12,281
THE AMOUNT OF MYC SPECIFICALLY N

5576
04:51:12,281 --> 04:51:13,582
OUR KNOCKOUT CELLS SUGGESTING IT

5577
04:51:13,582 --> 04:51:16,852
WAS EXAGGERATED mTOR ONE IN THE

5578
04:51:16,852 --> 04:51:19,054
MESS TEARIC LYMPH NODE.

5579
04:51:19,054 --> 04:51:24,459
SO AS IMMENSED, IN THE

5580
04:51:24,459 --> 04:51:26,328
INTRODUCTION -- MENTIONS, THE

5581
04:51:26,328 --> 04:51:28,330
CURRENT THINKING IS M TORQUE 1 D

5582
04:51:28,330 --> 04:51:31,033
MYC ARE INDUCED AS A RESULT OF

5583
04:51:31,033 --> 04:51:32,000
T-CELL DEPENDENT INTERACTIONS.

5584
04:51:32,000 --> 04:51:36,038
WE WANTED TO KNOW WHETHER OR NOT

5585
04:51:36,038 --> 04:51:37,573
T-CELL HELPS SOMEHOW COULD SUPPT

5586
04:51:37,573 --> 04:51:39,975
THE EXPANSION OF G ALPHA 13

5587
04:51:39,975 --> 04:51:41,577
DEFICIENT CELLS IN THE MESENTERC

5588
04:51:41,577 --> 04:51:42,377
LYMPH NODE.

5589
04:51:42,377 --> 04:51:47,382
TO DO THAT, WE TOOK OUR MIXED CE

5590
04:51:47,382 --> 04:51:51,453
ERAS AND DEPLETED THEM OF CD4

5591
04:51:51,453 --> 04:51:51,653
CELLS.

5592
04:51:51,653 --> 04:51:54,356
YOU CAN SEE HERE THAT IN THE

5593
04:51:54,356 --> 04:51:57,159
WILDTYPE CELLS IN THE MIXED

5594
04:51:57,159 --> 04:51:59,795
CHIMERA, THERE IS A LOSS OF

5595
04:51:59,795 --> 04:52:01,063
GERMINAL CENTER B CELLS WHEN WE

5596
04:52:01,063 --> 04:52:04,666
DEPLETE CD4 CELLS BUT THERE IS H

5597
04:52:04,666 --> 04:52:06,768
LESS OF A LOSS IN THE ABSENCE OG

5598
04:52:06,768 --> 04:52:10,839
ALPHA 13, SUGGESTING THAT THEREE

5599
04:52:10,839 --> 04:52:11,673
OTHER CUES OTHER THAN T-CELLS

5600
04:52:11,673 --> 04:52:13,475
SUPPORTING THEIR SURVIVAL AND/OR

5601
04:52:13,475 --> 04:52:16,178
EXPANSION IN THE MESENTERIC LYMH

5602
04:52:16,178 --> 04:52:16,612
NODE.

5603
04:52:16,612 --> 04:52:19,815
SO, AS I MENTIONED, IN THE ABSEE

5604
04:52:19,815 --> 04:52:24,086
OF G ALPHA 13 SIGNALING, CELLS N

5605
04:52:24,086 --> 04:52:26,388
EXPAND THROUGHOUT THE FOLLICLE D

5606
04:52:26,388 --> 04:52:28,090
ACTUALLY ENTER LYMPHATICS AND WE

5607
04:52:28,090 --> 04:52:31,093
WANTED TO KNOW IF THIS EXPANSION

5608
04:52:31,093 --> 04:52:34,096
COULD ALLOW THEM TO ACCESS

5609
04:52:34,096 --> 04:52:36,565
DIFFERENT ENVIRONMENTAL QUEUES T

5610
04:52:36,565 --> 04:52:37,766
WILDTYPE CELLS WOULD NORMALLY NT

5611
04:52:37,766 --> 04:52:38,500
SEE.

5612
04:52:38,500 --> 04:52:43,772
AND SO, WE INITIALLY DID

5613
04:52:43,772 --> 04:52:46,074
IMMUNOHISTOCHEMISTRY EXPERIMENT

5614
04:52:46,074 --> 04:52:47,976
WHERE WE STAINED GERMINAL CENTES

5615
04:52:47,976 --> 04:52:53,081
FROM WILDTYPE ANIMALS FOR MYC AS

5616
04:52:53,081 --> 04:52:53,882
WELL AS LYMPHATIC MARKERS.

5617
04:52:53,882 --> 04:52:56,184
SO THERE IS RARE AND POSITIVE CS

5618
04:52:56,184 --> 04:52:59,054
IN THE WILDTYPE THAT ARE POSITIE

5619
04:52:59,054 --> 04:53:00,489
FOR MYC BUT THERE IS A GREAT

5620
04:53:00,489 --> 04:53:02,090
INCREASE IN THE AMOUNT OF MYC

5621
04:53:02,090 --> 04:53:04,393
POSITIVE CELLS IN THE KNOCKOUT S

5622
04:53:04,393 --> 04:53:06,895
WE SEE, BUT STRIKINGLY OR

5623
04:53:06,895 --> 04:53:08,597
INTERESTINGLY WHAT WE ALSO FOUNS

5624
04:53:08,597 --> 04:53:10,198
THAT THERE WERE RARE GERMINAL

5625
04:53:10,198 --> 04:53:13,201
CENTER B CELLS IN LYMPHATICS THT

5626
04:53:13,201 --> 04:53:15,437
ALSO EXPRESSED MYC AND THAT IS

5627
04:53:15,437 --> 04:53:19,908
SHOWN IN THE INSETS THERE.

5628
04:53:19,908 --> 04:53:23,378
SO PREVIOUS WORK THAT WE HAD DOE

5629
04:53:23,378 --> 04:53:28,717
HAD SHOWN THAT A PRO MIGRATORY P

5630
04:53:28,717 --> 04:53:31,386
RECEPTOR, MEDIATES PART OF THIS

5631
04:53:31,386 --> 04:53:33,555
MIGRATION INTO THE OUTER FOLLICE

5632
04:53:33,555 --> 04:53:35,490
AS WELL AS THE LIMB AND WE WANTD

5633
04:53:35,490 --> 04:53:37,793
TO KNOW IF THAT COULD BE TARGETD

5634
04:53:37,793 --> 04:53:42,230
TO SPECIFICALLY REDUCE THE AMOUT

5635
04:53:42,230 --> 04:53:43,298
OF GERMINAL CENTER EXPANSION INE

5636
04:53:43,298 --> 04:53:44,599
ABSENCE OF G ALPHA 13.

5637
04:53:44,599 --> 04:53:47,302
SO TO DO THAT, WE GENERATED BONE

5638
04:53:47,302 --> 04:53:49,805
MARROW CHIMERAS IN WHICH THE BOE

5639
04:53:49,805 --> 04:53:51,606
MARROW WAS EITHER WILDTYPE BONE

5640
04:53:51,606 --> 04:53:53,809
MARROW THAT HAD A CONDITIONAL

5641
04:53:53,809 --> 04:53:56,712
EXPRESSION OF CAS9 IN GERMINAL

5642
04:53:56,712 --> 04:53:58,413
CENTER B CELLS WILDTYPE OR KNOCT

5643
04:53:58,413 --> 04:54:01,083
FOR G ALPHA 13 AND TARGETED THAT

5644
04:54:01,083 --> 04:54:05,187
WITH RETROVIRUS EXPRESSING GUIDE

5645
04:54:05,187 --> 04:54:05,387
RNAs.

5646
04:54:05,387 --> 04:54:07,289
SO YOU CAN SEE HERE THAT IN OUR

5647
04:54:07,289 --> 04:54:09,991
WILDTYPE BONE MARROW CHIMERAS, O

5648
04:54:09,991 --> 04:54:12,160
LOSS OF ABUNDANCE IN GENERALINAL

5649
04:54:12,160 --> 04:54:14,896
CENTER B CELLS COME S1PR3 IS

5650
04:54:14,896 --> 04:54:18,600
TARGETED BUT A STRIKING LOSS INE

5651
04:54:18,600 --> 04:54:21,803
MESENTERIC LYMPH NODES IN ANIMAS

5652
04:54:21,803 --> 04:54:23,305
THAT -- UNIQUE SURVIVAL FACTOR N

5653
04:54:23,305 --> 04:54:27,008
OUR G ALPHA 13 KNOCKOUTS.

5654
04:54:27,008 --> 04:54:29,911
ALSO INTERESTINGLY IN THE OTHER

5655
04:54:29,911 --> 04:54:32,447
ORGANS IN GERMINAL CENTERS OR

5656
04:54:32,447 --> 04:54:34,583
IMMUNIZED PERIPHERAL GERMINAL

5657
04:54:34,583 --> 04:54:35,751
CENTERS, THERE WAS NO DEPENDENC,

5658
04:54:35,751 --> 04:54:37,486
SUGGESTING THIS IS SOMETHING THT

5659
04:54:37,486 --> 04:54:39,321
WAS SPECIFICALLY HAPPENING IN TE

5660
04:54:39,321 --> 04:54:40,255
MESENTERIC LYMPH NODE.

5661
04:54:40,255 --> 04:54:43,225
SO TO GET AT WHAT OTHER MESENTEC

5662
04:54:43,225 --> 04:54:47,028
LYMPH NODE SPECIFIC QUEUES, WE

5663
04:54:47,028 --> 04:54:49,431
WANTED TO KNOW IF ANY OTHER GUT

5664
04:54:49,431 --> 04:54:50,465
DERIVED QUEUES MIGHT BE IMPORTAT

5665
04:54:50,465 --> 04:54:53,034
FOR PROMOTING THESE OUTGROWTHS.

5666
04:54:53,034 --> 04:54:54,536
SO THE FIRST QUESTION IS WHETHER

5667
04:54:54,536 --> 04:54:58,140
NOT MICROBIOTA IN THE SMALL

5668
04:54:58,140 --> 04:55:00,542
INTESTINE COULD BE SUPPORTING TE

5669
04:55:00,542 --> 04:55:02,644
EXPANSIONS OF THESE GERM.

5670
04:55:02,644 --> 04:55:07,249
SO WE WENT TO THE EFFORT OF

5671
04:55:07,249 --> 04:55:08,817
GENERATING GERM-FREE ANIMALS THT

5672
04:55:08,817 --> 04:55:11,920
LACKED G ALPHA 13.

5673
04:55:11,920 --> 04:55:16,525
AND WHAT WE FOUND IS THAT YOU CN

5674
04:55:16,525 --> 04:55:18,527
STILL SEE EXPANSION OF GERMINAL

5675
04:55:18,527 --> 04:55:19,227
CENTER B CELLS.

5676
04:55:19,227 --> 04:55:20,595
THESE ARE NOT MYC SETTINGS.

5677
04:55:20,595 --> 04:55:22,898
SO INCREASE IN GERMINAL CENTERSS

5678
04:55:22,898 --> 04:55:25,133
SIMILAR TO WHAT WE SEE IN THE SF

5679
04:55:25,133 --> 04:55:26,501
ANIMALS.

5680
04:55:26,501 --> 04:55:28,270
ADDITIONALLY, IF WE STAINED THEE

5681
04:55:28,270 --> 04:55:29,237
GERMINAL CENTER B CELLS FOR MYC,

5682
04:55:29,237 --> 04:55:33,041
YOU CAN SEE THERE WAS ALSO

5683
04:55:33,041 --> 04:55:35,744
INCREASED MYC IN THE ABSENCE OF

5684
04:55:35,744 --> 04:55:36,178
MICROBIOTA.

5685
04:55:36,178 --> 04:55:38,146
SO, WE WANTED TO GET AT OTHER

5686
04:55:38,146 --> 04:55:41,449
QUEUES THAT MIGHT BE SUPPORTING

5687
04:55:41,449 --> 04:55:43,251
THIS SURVIVAL AND SIMPLISTICALLY

5688
04:55:43,251 --> 04:55:45,654
WHAT WE DECIDED TO DO IS FAST ME

5689
04:55:45,654 --> 04:55:46,721
FOR 24 HOURS.

5690
04:55:46,721 --> 04:55:49,558
SO WHEN WE DID THIS, WHAT WE FOD

5691
04:55:49,558 --> 04:55:51,660
IS THAT WHEREAS OUR WILDTYPE CES

5692
04:55:51,660 --> 04:55:53,061
WERE SOMEWHAT DECREASED, THERE S

5693
04:55:53,061 --> 04:55:54,930
A MUCH LARGER DECREASE IN THE

5694
04:55:54,930 --> 04:55:57,666
AMOUNT OF LOSS OF G ALPHA 13 CES

5695
04:55:57,666 --> 04:55:59,167
SUGGESTING SOMETHING IN THE DIET

5696
04:55:59,167 --> 04:56:00,769
WAS SPECIFICALLY SUPPORTING THE

5697
04:56:00,769 --> 04:56:04,639
EXPANSION OF G ALPHA 13 DEFICIET

5698
04:56:04,639 --> 04:56:05,774
CELLS.

5699
04:56:05,774 --> 04:56:08,376
SO, TO SUMMARIZE A LOT OF WORK,E

5700
04:56:08,376 --> 04:56:12,380
FOUND THAT DIETARY FAT OR DIETAY

5701
04:56:12,380 --> 04:56:15,884
GLUCOSE COULD NOT DIFFERENTIALLY

5702
04:56:15,884 --> 04:56:19,988
SUPPORT THESE CELLS IN VITRO OR

5703
04:56:19,988 --> 04:56:20,755
IN-VIVO.

5704
04:56:20,755 --> 04:56:24,059
AND WE LOOKED AT ALSO REGULATOR

5705
04:56:24,059 --> 04:56:26,161
DEPENDENT AMINO ACID SENSING ANE

5706
04:56:26,161 --> 04:56:28,463
DIDN'T THINK THAT WAS INVOLVED.

5707
04:56:28,463 --> 04:56:31,566
BUT WE DECIDED TO LOOK AT

5708
04:56:31,566 --> 04:56:31,833
GLUTAMINE.

5709
04:56:31,833 --> 04:56:34,369
SO GLUTAMINE IS NOT AN ESSENTIAL

5710
04:56:34,369 --> 04:56:36,872
AMINO ACID BUT IT CAN DRAMATICAY

5711
04:56:36,872 --> 04:56:39,441
SUPPORT mTOR ONE SIGNALING AS

5712
04:56:39,441 --> 04:56:41,476
WELL AS MYC EXPRESSION.

5713
04:56:41,476 --> 04:56:44,579
AND IT'S SENSING IS NOT CURRENTY

5714
04:56:44,579 --> 04:56:46,381
CLEAR WHAT IT'S INTRACELLULAR

5715
04:56:46,381 --> 04:56:47,883
SENSORS ARE BUT THEY ARE

5716
04:56:47,883 --> 04:56:50,785
INDEPENDENT OF THE REGULATOR

5717
04:56:50,785 --> 04:56:52,087
COMPLEX.

5718
04:56:52,087 --> 04:56:53,455
SO IN VITRO WE GREW CELLS THAT E

5719
04:56:53,455 --> 04:56:58,293
G ALPHA 13 DEFICIENT IN THE

5720
04:56:58,293 --> 04:56:59,060
PRESENCE OR ALPHENCE OF STIMULAN

5721
04:56:59,060 --> 04:57:00,996
AND ABSENCE OF GLUTAMINE YOU CAN

5722
04:57:00,996 --> 04:57:04,165
SEE THAT SIMILAR TO OUR RAPAMYCN

5723
04:57:04,165 --> 04:57:06,201
TREATMENT, WHEN WE LOSE GLUTAMIE

5724
04:57:06,201 --> 04:57:09,905
THERE IS DECREASED OUT GROWTHS G

5725
04:57:09,905 --> 04:57:11,973
ALPHA 13 DEFICIENT CELLS.

5726
04:57:11,973 --> 04:57:16,978
WE THEN DECIDED TO PUT MICE ON

5727
04:57:16,978 --> 04:57:18,280
DIETS IN WHICH ALL THE PROTEIN S

5728
04:57:18,280 --> 04:57:21,983
IN THE FORM OF AMINO ACIDS AND A

5729
04:57:21,983 --> 04:57:26,054
CONTROLLED DIET HAD GLUTAMINE AS

5730
04:57:26,054 --> 04:57:27,789
WELL AS BHUTANIC ACID.

5731
04:57:27,789 --> 04:57:33,428
OUR EXPERIMENTAL DIET LACKED

5732
04:57:33,428 --> 04:57:33,995
GLUTAMINE AND GLUTAMINE.

5733
04:57:33,995 --> 04:57:36,598
YOU CAN SEE HERE OUR CONTROL

5734
04:57:36,598 --> 04:57:39,301
ANIMALS, STRIKING  INCREASE IN

5735
04:57:39,301 --> 04:57:40,902
AMOUNT OF MYC EXPRESSION IN OURG

5736
04:57:40,902 --> 04:57:44,105
ALPHA 13 DEFICIENT CELLS AND THT

5737
04:57:44,105 --> 04:57:47,609
IS REDUCED IN MICE THAT ARE ON R

5738
04:57:47,609 --> 04:57:49,911
QE DEFICIENT DIET.

5739
04:57:49,911 --> 04:57:52,013
ADDITIONALLY WHEN WE LOOK AT

5740
04:57:52,013 --> 04:57:54,416
PROLIFERATION, AS ASSESSED BY A

5741
04:57:54,416 --> 04:57:57,886
30-MINUTE PULSE, WE CAN SEE HERE

5742
04:57:57,886 --> 04:58:01,222
THAT THERE IS A SELECTIVE LOSS F

5743
04:58:01,222 --> 04:58:02,624
PROLIFERATION IN OUR KNOCKOUT

5744
04:58:02,624 --> 04:58:02,857
ANIMALS.

5745
04:58:02,857 --> 04:58:04,926
AND WE ALSO DID THE CONVERSE

5746
04:58:04,926 --> 04:58:12,200
EXPERIMENT WHERE WE PUT ANIMALSN

5747
04:58:12,200 --> 04:58:15,337
ACCESS GLUTAMINE IN THEIR WATER.

5748
04:58:15,337 --> 04:58:16,705
THE OUTGROWTHS OF G ALPHA 13 CES

5749
04:58:16,705 --> 04:58:18,340
WERE EXAGGERATED WHEN WE DID THT

5750
04:58:18,340 --> 04:58:19,007
FOR THREE WEEKS.

5751
04:58:19,007 --> 04:58:23,511
SO YOU CAN SEE HERE WHEN WE DO T

5752
04:58:23,511 --> 04:58:25,780
THERE IS INCREASE IN THE ABUNDAE

5753
04:58:25,780 --> 04:58:28,216
OF G ALPHA 13 CELLS AND SLIGHT

5754
04:58:28,216 --> 04:58:30,018
REDUCTION IN WILDTYPE CELLS.

5755
04:58:30,018 --> 04:58:34,622
SO TO SUMMARIZE, WE THINK THAT G

5756
04:58:34,622 --> 04:58:38,426
ALPHA 13 LIMITS NUTRIENT-DRIVEN

5757
04:58:38,426 --> 04:58:41,262
EXPANSION AND MEAS TAKER LYMPH E

5758
04:58:41,262 --> 04:58:44,432
GERMINAL CENTER B CELLS VIA THE

5759
04:58:44,432 --> 04:58:45,867
SUPPRESSION OF M TORQUE 1 AND MC

5760
04:58:45,867 --> 04:58:48,303
IN THE MESENTERIC LYMPH NODE AND

5761
04:58:48,303 --> 04:58:50,138
THIS GREATER ACCESS TO NUTRIENTN

5762
04:58:50,138 --> 04:58:52,974
THE MESENTERIC LYMPH NODE COULD

5763
04:58:52,974 --> 04:58:56,344
CONTRIBUTE TO THE GUT TROPISM O-

5764
04:58:56,344 --> 04:58:59,080
OR THE TUMOR SUPPRESSIVE CAPACIY

5765
04:58:59,080 --> 04:59:01,950
OF G ALPHA 13.

5766
04:59:01,950 --> 04:59:04,219
SO THIS WORK WAS PRIMARILY DONEY

5767
04:59:04,219 --> 04:59:07,222
A VERY TALENTED POSTDOC IN MY LB

5768
04:59:07,222 --> 04:59:16,631
AND WE HAD A LOT OF HELP FROM TE

5769
04:59:16,631 --> 04:59:18,433
NCI AND OTHERS.

5770
04:59:18,433 --> 04:59:20,635
WITH THAT, I WILL TAKE ANY

5771
04:59:20,635 --> 04:59:21,302
QUESTIONS.

5772
04:59:21,302 --> 04:59:30,545
[ APPLAUSE ]

5773
04:59:30,545 --> 04:59:31,446
>> THANK YOU.

5774
04:59:31,446 --> 04:59:34,349
GREAT PRESENTATION.

5775
04:59:34,349 --> 04:59:36,151
MYC PLAYS A ESSENTIAL ROLE IN TE

5776
04:59:36,151 --> 04:59:38,253
HUGE METABOLIC -- BECAUSE OF

5777
04:59:38,253 --> 04:59:40,455
T-CELLS ASSUMING THIS IS THE PHE

5778
04:59:40,455 --> 04:59:42,724
OF THE B CELLS SO WHAT IS THE

5779
04:59:42,724 --> 04:59:44,559
CONSEQUENCES FOR THESE GERMINAL

5780
04:59:44,559 --> 04:59:45,260
CENTER B CELLS?

5781
04:59:45,260 --> 04:59:47,529
DO THEY HAVE ANY MODULATION OF

5782
04:59:47,529 --> 04:59:50,298
METABOLIC PROFILE AND WHAT IS TE

5783
04:59:50,298 --> 04:59:51,266
FUNCTIONAL CONSEQUENCES?

5784
04:59:51,266 --> 04:59:54,669
>> SO, WE HAVEN'T BEEN
ABLE TO O

5785
04:59:54,669 --> 04:59:55,837
METABOLOMICS OR ANYTHING BECAUSF

5786
04:59:55,837 --> 04:59:57,872
JUST THE NUMBER OF CELLS THAT IS

5787
04:59:57,872 --> 05:00:00,542
REQUIRED BUT WE THINK THAT THERS

5788
05:00:00,542 --> 05:00:01,643
ALTER METABOLISM.

5789
05:00:01,643 --> 05:00:03,144
SO THE FIRST PIECE OF EVIDENCE E

5790
05:00:03,144 --> 05:00:07,315
HAVE IS -- SO, MOST GERMINAL CER

5791
05:00:07,315 --> 05:00:13,855
B CELLS REQUIRE FATTY ACID

5792
05:00:13,855 --> 05:00:15,957
OXIDATION TO SUPPORT ENERGY.

5793
05:00:15,957 --> 05:00:18,359
WILDTYPE CELLS DO BUT G ALPHA 13

5794
05:00:18,359 --> 05:00:19,661
CELLS DON'T AND WE HAVE DONE THT

5795
05:00:19,661 --> 05:00:22,363
IN A NUMBER OF DIFFERENT WAYS.

5796
05:00:22,363 --> 05:00:27,268
WE GENERATED CAS9 CHIMERAS, WHEE

5797
05:00:27,268 --> 05:00:32,540
WE KNOCKOUT THE ENZYME RESPONSIE

5798
05:00:32,540 --> 05:00:36,744
FOR TRANSPORT.

5799
05:00:36,744 --> 05:00:39,447
AND SO ADDITIONALLY THEY DON'T M

5800
05:00:39,447 --> 05:00:44,652
TO DEPEND UPON GLUCOSE AS MUCH.

5801
05:00:44,652 --> 05:00:49,858
WHEN WE KNOCKOUT GLUTE 1, WE SEE

5802
05:00:49,858 --> 05:00:52,360
DEPENDENCE IN WILDTYPE BUT NOT

5803
05:00:52,360 --> 05:00:52,627
KNOCKOUT.

5804
05:00:52,627 --> 05:00:55,563
I CAN'T GIVE YOU SPECIFIC EXAMPS

5805
05:00:55,563 --> 05:00:57,365
OF WHAT OTHER THINGS --

5806
05:00:57,365 --> 05:00:57,799
>> BEAUTIFUL TALK.

5807
05:00:57,799 --> 05:01:03,171
I HAD A QUESTION REGARDING -- YU

5808
05:01:03,171 --> 05:01:04,472
SHOWED IN YOUR SLIDE THERE WAS

5809
05:01:04,472 --> 05:01:06,474
REALLY NO DIFFERENCE BUT I WONDD

5810
05:01:06,474 --> 05:01:08,476
PERHAPS HAVE YOU LOOKED AT PROXL

5811
05:01:08,476 --> 05:01:10,678
TO DISTAL IN TERMS OF SMALL

5812
05:01:10,678 --> 05:01:12,680
INTESTINE IF THERE IS ANY GRADIT

5813
05:01:12,680 --> 05:01:14,883
OF --

5814
05:01:14,883 --> 05:01:17,886
>> SO THERE ARE OUTGROWTHS
THAT

5815
05:01:17,886 --> 05:01:18,953
HAPPEN IN THE MYCS CHIMERA.

5816
05:01:18,953 --> 05:01:20,355
I DIDN'T SHOW THAT.

5817
05:01:20,355 --> 05:01:24,959
IT'S AN AIR MEDIATED EFFECT.

5818
05:01:24,959 --> 05:01:26,861
THE REASON -- AND NONE OF THE ME

5819
05:01:26,861 --> 05:01:30,532
DEVELOPED TUMORS IN THEIR BATCH.

5820
05:01:30,532 --> 05:01:34,035
AS YOU PROBABLY KNOW, THE AN ATE

5821
05:01:34,035 --> 05:01:36,070
OF THE PAIR PATCH IS UNIQUE IN W

5822
05:01:36,070 --> 05:01:37,672
THE LIGHT ZONE AND DARK ZONE ARE

5823
05:01:37,672 --> 05:01:41,176
FLIPPED AND ADDITIONALLY THERE S

5824
05:01:41,176 --> 05:01:43,778
NO LYMPHATICS IN THE PAIRS PATC.

5825
05:01:43,778 --> 05:01:45,380
SO THE DISTANCE A METABOLITE WOD

5826
05:01:45,380 --> 05:01:47,382
HAVE TO TRAVEL IN THE PAIRS PATH

5827
05:01:47,382 --> 05:01:50,285
IS LARGER THAN IN THE MEAS TEARC

5828
05:01:50,285 --> 05:01:51,619
LYMPH NODE IN TERMS OF ACCESS.

5829
05:01:51,619 --> 05:01:53,288
I THINK THAT MIGHT BE THE REASON

5830
05:01:53,288 --> 05:01:55,590
BUT WE HAVEN'T EXPLICITLY SHOWN

5831
05:01:55,590 --> 05:01:55,790
THAT.

5832
05:01:55,790 --> 05:01:58,393
>> AND SECOND QUESTION.

5833
05:01:58,393 --> 05:01:59,727
REGARDING JOURNALS AND REACTION

5834
05:01:59,727 --> 05:02:01,229
HAVE YOU LOOKED AT CELL CONTENTN

5835
05:02:01,229 --> 05:02:04,599
BONE MARROW, LET'S SAY, AFTER DT

5836
05:02:04,599 --> 05:02:06,201
AND INTERVENTIONS --

5837
05:02:06,201 --> 05:02:07,902
>> SO I DIDN'T SHOW THAT
HERE BT

5838
05:02:07,902 --> 05:02:09,671
WE DON'T THINK THAT THERE IS

5839
05:02:09,671 --> 05:02:11,873
GREATER GENERATION OF EITHER PLA

5840
05:02:11,873 --> 05:02:13,274
CELLS OR MEMORY CELLS IN THE

5841
05:02:13,274 --> 05:02:14,876
ABSENCE OF G ALPHA 13.

5842
05:02:14,876 --> 05:02:16,778
SO WHEN WE KNOCK IT OUT IN A FAE

5843
05:02:16,778 --> 05:02:21,149
MAPPING APPROACH WE SEE GREATER

5844
05:02:21,149 --> 05:02:24,385
CLONAL LONGEVITY WITHOUT ANY

5845
05:02:24,385 --> 05:02:27,288
INCREASE IN THE AMOUNT OF MEMORY

5846
05:02:27,288 --> 05:02:29,290
CELLS AND LIKELY PLASMA CELLS

5847
05:02:29,290 --> 05:02:31,459
PRODUCED FROM THOSE GERMINAL

5848
05:02:31,459 --> 05:02:31,693
CENTERS.

5849
05:02:31,693 --> 05:02:36,798
>> THANK YOU, REALLY COOL.

5850
05:02:36,798 --> 05:02:37,799
>> LOVELY TALK.

5851
05:02:37,799 --> 05:02:40,602
SO I WAS WONDERING WHEN YOU STAE

5852
05:02:40,602 --> 05:02:42,003
THE WHOLE THING, DEPRIVE OF

5853
05:02:42,003 --> 05:02:45,206
NUTRITION, OR WHEN YOU'RE ADDING

5854
05:02:45,206 --> 05:02:48,376
RAPAMYCIN, ONE OF THE PATHWAYS,

5855
05:02:48,376 --> 05:02:50,912
LIKE MOST -- ARTIFICIAL INDUCTI.

5856
05:02:50,912 --> 05:02:52,780
HOW DOES THAT EFFECT THIS WHOLE

5857
05:02:52,780 --> 05:02:55,083
THING PARTICULARLY SHOWN TO BE

5858
05:02:55,083 --> 05:02:58,586
RECENT MEMORY AND -- HOW IS THAT

5859
05:02:58,586 --> 05:03:00,221
WORKING HERE?

5860
05:03:00,221 --> 05:03:01,823
>> SO, ARE YOU ASKING HOW
WE'RE

5861
05:03:01,823 --> 05:03:06,060
MAKING SURE THAT WE'RE NOT INDUG

5862
05:03:06,060 --> 05:03:07,595
MULTI.

5863
05:03:07,595 --> 05:03:09,497
>> STRONG EFFECT IN PHASIA
--

5864
05:03:09,497 --> 05:03:11,499
>> IN VITRO WHEN WE
STIMULATE WH

5865
05:03:11,499 --> 05:03:15,503
G ALPHA 13 IN OUR CELL LINES, WE

5866
05:03:15,503 --> 05:03:18,206
DON'T INDUCE ANY AUTOPHAGY THROH

5867
05:03:18,206 --> 05:03:18,973
G ALPHA 13.

5868
05:03:18,973 --> 05:03:22,510
I DON'T KNOW WHY THAT IS, IF WEE

5869
05:03:22,510 --> 05:03:23,811
INHIBITING mTOR 1 BUT WE DON'T

5870
05:03:23,811 --> 05:03:26,214
SEE ANY EVIDENCE.

5871
05:03:26,214 --> 05:03:29,017
WE VIOLENT DONE AS MUCH IN-VIVO.

5872
05:03:29,017 --> 05:03:29,784
>> VERY NICE.

5873
05:03:29,784 --> 05:03:32,020
DID YOU LOOK AT EXPRESSION OF

5874
05:03:32,020 --> 05:03:37,625
NUTRIENT TRANSPORTERS IN THE

5875
05:03:37,625 --> 05:03:37,892
KNOCKOUT?

5876
05:03:37,892 --> 05:03:39,027
>> SO, WE'VE TRIED TO TAKE
THE

5877
05:03:39,027 --> 05:03:41,496
OPPOSITE APPROACH AND KNOCKING T

5878
05:03:41,496 --> 05:03:43,798
CANDIDATE GLUTAMINE TRANSPORTERN

5879
05:03:43,798 --> 05:03:46,100
OUR BONE MARROW CHIMERAS AND WE

5880
05:03:46,100 --> 05:03:48,803
HAVEN'T BEEN ABLE TO SEE A SPECC

5881
05:03:48,803 --> 05:03:51,105
EFFECT WITH SINGLE TRANSPORTERS.

5882
05:03:51,105 --> 05:03:54,108
BUT THERE IS A LOT OF -- AT LEAT

5883
05:03:54,108 --> 05:03:55,777
SIX EXPRESSED IN GERMINAL CENTE.

5884
05:03:55,777 --> 05:03:57,512
>> DO YOU HAVE ANY IDEA OF
THE

5885
05:03:57,512 --> 05:03:59,614
DOWNSTREAM SIGNALING PATHWAYS TT

5886
05:03:59,614 --> 05:04:01,616
MAYBE EFFECTING --

5887
05:04:01,616 --> 05:04:02,517
>> BETWEEN mTOR 1?

5888
05:04:02,517 --> 05:04:04,919
THAT'S BEEN REALLY TOUGH.

5889
05:04:04,919 --> 05:04:10,525
WE DON'T KNOW.

5890
05:04:10,525 --> 05:04:11,826
>> COULD I ASK A QUESTION.

5891
05:04:11,826 --> 05:04:15,029
COULD YOU REMIND US WHAT ARE THE

5892
05:04:15,029 --> 05:04:20,368
EFFECTS OF THE G ALPHA 13 EFFECS

5893
05:04:20,368 --> 05:04:20,935
IN THE KNOCKOUTS --

5894
05:04:20,935 --> 05:04:22,236
>> THIS IS IT A
CONDITIONAL

5895
05:04:22,236 --> 05:04:25,073
KNOCKOUT SO I HAVE NEVER DONE

5896
05:04:25,073 --> 05:04:31,412
ANYTHING OUTSIDE OF B CELLS.

5897
05:04:31,412 --> 05:04:34,048
SO, OFF THE TOP OF MY -- I'M

5898
05:04:34,048 --> 05:04:35,850
DRAWING A BLANK.

5899
05:04:35,850 --> 05:04:36,851
>> NO PROBLEM.

5900
05:04:36,851 --> 05:04:39,253
>> SO WE THINK T ALPHA 13
IS

5901
05:04:39,253 --> 05:04:43,458
IMPORTANT IN -- SO S1PR2 IS THE

5902
05:04:43,458 --> 05:04:45,893
RECEPTOR EXPRESSED ON GIRLINAL

5903
05:04:45,893 --> 05:04:49,263
CENTER AND WHEN YOU KNOCK IT OUN

5904
05:04:49,263 --> 05:04:51,566
T-CELLS, WE THINK THAT THEY CANT

5905
05:04:51,566 --> 05:04:54,769
LOCALIZE TO THE GERMINAL CENTER.

5906
05:04:54,769 --> 05:04:57,338
IT SHOULDN'T HAVE AN EFFECT.

5907
05:04:57,338 --> 05:04:57,872
>> THANK YOU VERY MUCH.

5908
05:04:57,872 --> 05:04:58,940
AND THANKS TO ALL THE SPEAKERS N

5909
05:04:58,940 --> 05:04:59,407
THIS SESSION.

5910
05:04:59,407 --> 05:05:01,676
AND I THINK WE HAVE A BREAK.

5911
05:05:01,676 --> 05:05:06,347
DO YOU KNOW -- SO WE RETURN AT 5

5912
05:05:06,347 --> 05:05:09,250
SHARP FOR THE TRIUMPHANT CONCLUN

5913
05:05:09,250 --> 05:05:12,453
OF THIS AMAZING, MARVELOUS

5914
05:05:12,453 --> 05:05:12,720
SYMPOSIUM.

5915
05:05:12,720 --> 05:05:18,243
THANK YOU.

5916
05:05:18,243 --> 05:05:20,645
>> AS YOU ALL KNOW -- IF
YOU DOT

5917
05:05:20,645 --> 05:05:22,347
WE'LL BE HAPPY TO INTRODUCE YOU

5918
05:05:22,347 --> 05:05:23,281
THE CONCEPT.

5919
05:05:23,281 --> 05:05:26,151
BUT ORGANIZING A MEETING DOES CE

5920
05:05:26,151 --> 05:05:29,454
WITH SOME WONDERFUL CHANCES,

5921
05:05:29,454 --> 05:05:32,424
RESPONSIBILITIES, E-MAILS AND

5922
05:05:32,424 --> 05:05:37,295
ORGANIZATION.

5923
05:05:37,295 --> 05:05:40,565
ANDULE OF US ARE REALLY LUCKY TO

5924
05:05:40,565 --> 05:05:41,866
HAVE THIS WONDERFUL TEAM OF PEOE

5925
05:05:41,866 --> 05:05:44,669
WHO ARE HELPING US.

5926
05:05:44,669 --> 05:05:46,371
SO THAT MEANT WE DIDN'T HAVE TOO

5927
05:05:46,371 --> 05:05:47,939
LOTS AND LOTS OF DIFFERENT THIN.

5928
05:05:47,939 --> 05:05:50,642
THEY REALLY MANAGED TO GET THISL

5929
05:05:50,642 --> 05:05:53,678
OFF AND WE OWE YOU A HUGE GRATIE

5930
05:05:53,678 --> 05:05:54,546
OF THANKS AND I'D LIKE TO THANK

5931
05:05:54,546 --> 05:05:56,748
JULIA AND HER TEAM AND OUR

5932
05:05:56,748 --> 05:05:57,515
WONDERFUL SUPPORT.

5933
05:05:57,515 --> 05:05:59,184
SO WE HAVE SOMETHING FOR YOU ANE

5934
05:05:59,184 --> 05:06:02,654
ARE REALLY HAPPY IF YOU CAN COME

5935
05:06:02,654 --> 05:06:03,521
CELEBRATE TOGETHER.

5936
05:06:03,521 --> 05:06:13,731
[ APPLAUSE ]

5937
05:06:28,279 --> 05:06:28,446
>> WOW!

5938
05:06:28,446 --> 05:06:33,718
THANK YOU!

5939
05:06:33,718 --> 05:06:34,252
[ APPLAUSE ]

5940
05:06:34,252 --> 05:06:36,154
FOR THOSE WHO ARE SPEAKERS, THEY

5941
05:06:36,154 --> 05:06:39,257
KNOW JUST HOW MUCH WE WERE ABLEO

5942
05:06:39,257 --> 05:06:41,593
RELY ON THIS WONDERFUL TEAM ANDO

5943
05:06:41,593 --> 05:06:42,660
HAVE EVERYTHING ORGANIZED.

5944
05:06:42,660 --> 05:06:44,662
SO AGAIN, A HUGE THANKS FOR ALLU

5945
05:06:44,662 --> 05:06:44,863
DO.

5946
05:06:44,863 --> 05:06:47,599
WE KNOW THAT BASICALLY WHAT HAPS

5947
05:06:47,599 --> 05:06:50,101
IS EVERY TIME THERE IS A PROBLE,

5948
05:06:50,101 --> 05:06:52,370
EVERY TIME THE SLIDE FLICKED ORA

5949
05:06:52,370 --> 05:06:56,541
NOISE OR SOMETHING -- JULIA I'MN

5950
05:06:56,541 --> 05:06:56,774
TROUBLE!

5951
05:06:56,774 --> 05:06:58,409
SO WE BITCH A LOT BUT WE DO WANO

5952
05:06:58,409 --> 05:07:00,678
ALSO SAY THANK YOU.

5953
05:07:00,678 --> 05:07:02,514
SO THANK YOU VERY MUCH FOR ALL R

5954
05:07:02,514 --> 05:07:02,714
HELP.

5955
05:07:02,714 --> 05:07:12,924
[ APPLAUSE ]

5956
05:07:19,464 --> 05:07:20,598
>> WELCOME TO THE LAST
SESSION F

5957
05:07:20,598 --> 05:07:24,102
THIS REALLY TERRIFIC MEETING ON

5958
05:07:24,102 --> 05:07:26,504
CANCER IMMUNOLOGY PART II.

5959
05:07:26,504 --> 05:07:29,908
OUR FIRST SPEAKER IS DARIO VIGN.

5960
05:07:29,908 --> 05:07:32,977
I'M AFRAID WE DON'T HAVE ANY

5961
05:07:32,977 --> 05:07:34,879
FLOWERS FOR YOU BUT --

5962
05:07:34,879 --> 05:07:36,381
>> SHOULD I LEAVE NOW?

5963
05:07:36,381 --> 05:07:38,683
>> WE ARE LOOKING FORWARD
TO

5964
05:07:38,683 --> 05:07:40,785
HEARING ABOUT LAG3.

5965
05:07:40,785 --> 05:07:41,052
SO DARIO.

5966
05:07:41,052 --> 05:07:45,590
>> THANK YOU.

5967
05:07:45,590 --> 05:07:46,491
THANK YOU VERY MUCH.

5968
05:07:46,491 --> 05:07:48,426
FIRSTLY, THANKS SO MUCH TO THE

5969
05:07:48,426 --> 05:07:50,595
ORGANIZERS, REALLY A PLEASURE TE

5970
05:07:50,595 --> 05:07:52,196
HERE TO HAVE THIS OPPORTUNITY TO

5971
05:07:52,196 --> 05:07:53,097
TALK TO YOU.

5972
05:07:53,097 --> 05:07:56,401
IT'S BEEN A FANTASTIC MEETING.

5973
05:07:56,401 --> 05:07:57,602
HOPEFULLY IT DOESN'T GO DOWNHILL

5974
05:07:57,602 --> 05:07:58,503
FROM HERE.

5975
05:07:58,503 --> 05:08:01,005
I'M GOING TO TALK TO YOU ABOUT

5976
05:08:01,005 --> 05:08:01,205
LAG3.

5977
05:08:01,205 --> 05:08:04,275
I'M GOING TO TAKE A LITTLE BIT A

5978
05:08:04,275 --> 05:08:06,311
LEAF OUT OF CLAUDIA'S BOOK AND T

5979
05:08:06,311 --> 05:08:08,112
TALK DEEPLY ABOUT ONE QUESTION R

5980
05:08:08,112 --> 05:08:11,015
ONE PROJECT, BUT RATHER START WH

5981
05:08:11,015 --> 05:08:14,786
AN OVERVIEW OF WHAT LAG3 DOES, R

5982
05:08:14,786 --> 05:08:16,821
THOSE WHO DON'T KNOW MUCH ABOUT,

5983
05:08:16,821 --> 05:08:18,823
TALK A LITTLE BIT ABOUT A RECENT

5984
05:08:18,823 --> 05:08:20,825
PAPER THAT CAME OUT, VERY, VERY

5985
05:08:20,825 --> 05:08:22,327
BRIEFLY, AND THEN MOST OF THE RT

5986
05:08:22,327 --> 05:08:24,696
WILL BE TALKING ABOUT TWO

5987
05:08:24,696 --> 05:08:27,131
UNPUBLISHED STORIES, HOPEFULLY Y

5988
05:08:27,131 --> 05:08:29,901
WON'T BE UNPUBLISHED FOR TOO MUH

5989
05:08:29,901 --> 05:08:30,134
LONGER.

5990
05:08:30,134 --> 05:08:31,736
AND TRY AND THROW IN A LITTLE BT

5991
05:08:31,736 --> 05:08:34,639
OF PROVOCATIVE COMMENTS AND

5992
05:08:34,639 --> 05:08:37,909
STATEMENTS TO INDUCE SOME THOUGT

5993
05:08:37,909 --> 05:08:39,410
PROVOKING CONSEQUENCES AND MAYBE

5994
05:08:39,410 --> 05:08:40,545
GET YOU A LITTLE BIT EXCITED ABT

5995
05:08:40,545 --> 05:08:43,815
LAG3 AND HOW IT MIGHT BE PLAYING

5996
05:08:43,815 --> 05:08:46,951
ROLLS IN YOUR FAVORITE PROJECTS.

5997
05:08:46,951 --> 05:08:48,720
THESE ARE MY DISCLOSURES.

5998
05:08:48,720 --> 05:08:50,321
OBVIOUSLY I'LL TALK ABOUT LAG3 O

5999
05:08:50,321 --> 05:08:53,925
IF I SEEM OVERLY ENTHUSIASTIC OR

6000
05:08:53,925 --> 05:08:56,260
CONFLICTED, YOU'LL UNDERSTAND W.

6001
05:08:56,260 --> 05:09:00,732
SO LAG3 IS IN MANY WAYS LIKE OTR

6002
05:09:00,732 --> 05:09:03,768
INHIBITORY RECEPTORS, LIMITS T-L

6003
05:09:03,768 --> 05:09:05,837
FUNCTION, HOMEOSTASIS AND A VARY

6004
05:09:05,837 --> 05:09:08,539
OF ACTIVITIES T HAS ROLLS IN OTR

6005
05:09:08,539 --> 05:09:10,441
CELL TYPES BUT I'M REALLY GOINGO

6006
05:09:10,441 --> 05:09:13,311
FOCUS ON T-CELLS TODAY.

6007
05:09:13,311 --> 05:09:16,748
IMPACTS TCR SIGNALING LIKE PD-1T

6008
05:09:16,748 --> 05:09:19,450
UNTIL RECENTLY AN UNKNOWN MODE F

6009
05:09:19,450 --> 05:09:20,985
FUNCTION, WHICH I'LL TALK ABOUTN

6010
05:09:20,985 --> 05:09:22,020
A LITTLE BIT.

6011
05:09:22,020 --> 05:09:25,256
IT HAS A VARIETY OF LIGANDS WITH

6012
05:09:25,256 --> 05:09:29,661
SOME CONTROVERSIES WHICH I WON'O

6013
05:09:29,661 --> 05:09:32,964
INTO, BUT CONSIDERED CANONICAL

6014
05:09:32,964 --> 05:09:33,197
LIGANDS.

6015
05:09:33,197 --> 05:09:37,135
AND RAPIDLY SHED BY PROTEASES AD

6016
05:09:37,135 --> 05:09:38,536
I'LL TALK ABOUT THAT BRIEFLY, WH

6017
05:09:38,536 --> 05:09:41,172
IS SORT OF UNUSUAL COMPARED TO E

6018
05:09:41,172 --> 05:09:43,041
OTHER INHIBITORY RECEPTORS.

6019
05:09:43,041 --> 05:09:45,143
IT IS, AS YOU HAVE HEARD,

6020
05:09:45,143 --> 05:09:48,046
ESPECIALLY NICELY FROM PAM AND

6021
05:09:48,046 --> 05:09:51,949
TANLY'S PRESENTATIONS AND OTHER,

6022
05:09:51,949 --> 05:09:53,651
INHIBITORY RECEPTOR AS PART OF A

6023
05:09:53,651 --> 05:09:55,953
COHORT OF INHIBITORY RECEPTORS T

6024
05:09:55,953 --> 05:09:57,855
ARE UPREGULATED ON CHRONICALLY

6025
05:09:57,855 --> 05:09:59,924
EXHAUSTED T-CELLS IN CANCER AND

6026
05:09:59,924 --> 05:10:04,062
VIRAL INFECTIONS.

6027
05:10:04,062 --> 05:10:06,464
WE SHOWED RECENTLY OR A NUMBER F

6028
05:10:06,464 --> 05:10:07,999
YEARS AGO, FIRST IN COLLABORATIN

6029
05:10:07,999 --> 05:10:12,770
WITH JOHN WEARY IN CHRONIC LCMV

6030
05:10:12,770 --> 05:10:14,472
CLONED 13 MODELS AND SUBSEQUENTY

6031
05:10:14,472 --> 05:10:18,376
IN TUMOR MODELS, THE COMBINATORL

6032
05:10:18,376 --> 05:10:21,345
BLOCKADE OF LAG3 IN PD-1 CAN GIE

6033
05:10:21,345 --> 05:10:22,880
RISE TO SYNERGISTIC ACTIVITY.

6034
05:10:22,880 --> 05:10:25,016
TO GIVE YOU A SENSE WHAT HAVE TT

6035
05:10:25,016 --> 05:10:28,586
ACCIDENT LOO LIKE, THESE ARE

6036
05:10:28,586 --> 05:10:29,220
CLASSIC TUMOR GROWTH MODELS EACH

6037
05:10:29,220 --> 05:10:29,821
LINES AND INDIVIDUALS MOUSE.

6038
05:10:29,821 --> 05:10:31,889
AND YOU CAN SEE WITH THESE TUMOR

6039
05:10:31,889 --> 05:10:34,659
TYPES THE TUMORS GROW OUT.

6040
05:10:34,659 --> 05:10:38,096
SINGLE MODALITY ANTI-LAG3 OR PD1

6041
05:10:38,096 --> 05:10:40,998
GIVES RISE TO SOME TUMOR REDUCTS

6042
05:10:40,998 --> 05:10:43,868
BUT RELATIVELY LIMITED TO A

6043
05:10:43,868 --> 05:10:44,135
CLEARANCE.

6044
05:10:44,135 --> 05:10:46,170
AND THE IT'S ONLY REALLY WHEN YU

6045
05:10:46,170 --> 05:10:49,073
SEE THE COMBINATION THAT YOU'RE

6046
05:10:49,073 --> 05:10:51,709
GETTING SIGNIFICANT TUMOR

6047
05:10:51,709 --> 05:10:51,976
CLEARANCE.

6048
05:10:51,976 --> 05:10:55,480
SO THIS COMBINATORIAL SYNERGISTC

6049
05:10:55,480 --> 05:10:57,982
ACTIVITY INDUCED A LOT OF INTERT

6050
05:10:57,982 --> 05:11:04,455
IN DEVELOPING CLINICAL ANTIBODI[

6051
05:11:04,455 --> 05:11:04,756
INAUDIBLE ]

6052
05:11:04,756 --> 05:11:07,291
TO ENTER THE CLINIC, THERE ARE W

6053
05:11:07,291 --> 05:11:09,293
OVER 16 DIFFERENT ANTIBODIES INE

6054
05:11:09,293 --> 05:11:13,197
CLINIC EITHER MONOSPECIFIC LAG3

6055
05:11:13,197 --> 05:11:15,600
ANTIBODIES, SPIKE SPECIFICS, THE

6056
05:11:15,600 --> 05:11:18,603
MOST ADVANCED IN TERMS OF

6057
05:11:18,603 --> 05:11:21,139
REGISTRATIONAL CLINICAL ACTIVITY

6058
05:11:21,139 --> 05:11:26,177
WAS RELATIVITY 47 -- [ INAUDIBL]

6059
05:11:26,177 --> 05:11:28,012
PHASE III TRIAL IN TREATMENT NAE

6060
05:11:28,012 --> 05:11:31,482
METASTATIC MELANOMA PATIENTS THT

6061
05:11:31,482 --> 05:11:33,785
MET ENDPOINT WITH PROGRESSION-FE

6062
05:11:33,785 --> 05:11:36,521
SURVIVAL IT WAS REPORTED BY THEW

6063
05:11:36,521 --> 05:11:39,791
ENGLAND JOURNAL OF MEDICINE THED

6064
05:11:39,791 --> 05:11:42,794
OF LAST YEAR.

6065
05:11:42,794 --> 05:11:45,396
AND THEN SUBSEQUENT DATA SHOWING

6066
05:11:45,396 --> 05:11:47,899
THAT IN THE NEW ADVENT SETTING T

6067
05:11:47,899 --> 05:11:50,201
HAD EVEN A GREATER EFFICACY, AT

6068
05:11:50,201 --> 05:11:52,904
LEAST IN TERMS OF PATHOLOGICAL

6069
05:11:52,904 --> 05:11:54,705
RESPONSE IN RECEPTIBLE MELANOMA.

6070
05:11:54,705 --> 05:11:59,110
THIS LED TO FDA APPROVAL OF FIXD

6071
05:11:59,110 --> 05:12:01,012
DOSE COMBINATION OF DUO LAG FORE

6072
05:12:01,012 --> 05:12:04,015
TREATMENT OF UNRECEPTAL AND

6073
05:12:04,015 --> 05:12:06,017
METASTATIC MELANOMA APPROVED ATE

6074
05:12:06,017 --> 05:12:08,219
BEGINNING OF LAST YEAR.

6075
05:12:08,219 --> 05:12:12,089
SO WITH ALL OF THIS EXCITEMENT D

6076
05:12:12,089 --> 05:12:14,325
CLINICAL ACTIVITY, I THINK MOSTF

6077
05:12:14,325 --> 05:12:16,427
US APPRECIATE THAT WE STILL HAVN

6078
05:12:16,427 --> 05:12:19,230
MANY WAYS A LONG WAY TO GO, MANF

6079
05:12:19,230 --> 05:12:21,833
THE CHALLENGES THAT FACE LAG3 AE

6080
05:12:21,833 --> 05:12:24,135
THE SAME AS FACED WITH PD-1, AND

6081
05:12:24,135 --> 05:12:25,803
THAT IS THE REALITY IS WE STILL

6082
05:12:25,803 --> 05:12:28,906
DON'T REALLY UNDERSTAND HOW IT

6083
05:12:28,906 --> 05:12:29,106
WORKS.

6084
05:12:29,106 --> 05:12:31,209
AND YOU CAN THINK ABOUT, WHAT DS

6085
05:12:31,209 --> 05:12:32,410
THAT MEAN?

6086
05:12:32,410 --> 05:12:34,345
THINK ABOUT HOW SOMETHING WORKS

6087
05:12:34,345 --> 05:12:36,514
EITHER INSIDE THE CELL OR OUTWAD

6088
05:12:36,514 --> 05:12:37,815
CONSEQUENCES OF THAT.

6089
05:12:37,815 --> 05:12:38,716
SO I'LL TALK A LITTLE BIT ABOUT

6090
05:12:38,716 --> 05:12:39,350
THAT TODAY.

6091
05:12:39,350 --> 05:12:42,220
SO FIRSTLY, VERY BRIEFLY ABOUT A

6092
05:12:42,220 --> 05:12:44,422
PAPER THAT IS ALREADY PUBLISHEDN

6093
05:12:44,422 --> 05:12:46,724
THE INHIBITORY SIGNALS BRAS IT S

6094
05:12:46,724 --> 05:12:48,125
RELEVANCE TO WHAT I'M GOING TO K

6095
05:12:48,125 --> 05:12:49,827
ABOUT, AND THEN TALK A LITTLE BT

6096
05:12:49,827 --> 05:12:52,029
MORE -- AGAIN ONLY RELATIVELY

6097
05:12:52,029 --> 05:12:53,831
BRIEFLY WITH THE TIME AVAILABLE,

6098
05:12:53,831 --> 05:12:55,333
WITH SOME MOUSE STUDIES AND THET

6099
05:12:55,333 --> 05:12:58,135
THE END WITH SOME HUMAN STUDIES.

6100
05:12:58,135 --> 05:13:00,638
SO, HOW DOES LAG3 WORK?

6101
05:13:00,638 --> 05:13:02,440
AND THIS IS AN UNFORTUNATELY VEY

6102
05:13:02,440 --> 05:13:04,942
LONG STORY THAT TOOK ALMOST 10

6103
05:13:04,942 --> 05:13:07,044
YEARS TO COMPLETE.

6104
05:13:07,044 --> 05:13:09,146
PERHAPS YOU'LL SEE A LITTLE BIT

6105
05:13:09,146 --> 05:13:09,614
WHY.

6106
05:13:09,614 --> 05:13:12,350
DRIVEN BY TWO FANTASTIC PEOPLE N

6107
05:13:12,350 --> 05:13:15,653
THE LAB, POSTDOC IN THE LAB, ATE

6108
05:13:15,653 --> 05:13:19,624
TAIL END EVER MY TIME AT ACCEPT

6109
05:13:19,624 --> 05:13:21,726
JUDE, CRAIG, AND A LOT OF BENEFT

6110
05:13:21,726 --> 05:13:23,261
AND A LOT OF PRAISE FROM A LOT F

6111
05:13:23,261 --> 05:13:25,363
THE LAG3 STUFF THAT WE HAVE DON.

6112
05:13:25,363 --> 05:13:27,531
HE HADS BEEN IN THE LAB FOR 25

6113
05:13:27,531 --> 05:13:30,668
YEARS WORKING ON LAG3 AND SENIOR

6114
05:13:30,668 --> 05:13:31,636
AUTHOR ON THIS PAPER.

6115
05:13:31,636 --> 05:13:33,471
AND WE ASKED TWO BASIC QUESTION.

6116
05:13:33,471 --> 05:13:37,041
HOW DOES LAG3 MEDIATE INHIBITORY

6117
05:13:37,041 --> 05:13:37,308
ACTIVITY?

6118
05:13:37,308 --> 05:13:38,542
AND ALSO TRYING TO UNDERSTAND

6119
05:13:38,542 --> 05:13:40,845
WHETHER THE MHC CLASS TWO WAS

6120
05:13:40,845 --> 05:13:43,347
REALLY REQUIRED FOR LAG3 FUNCTI?

6121
05:13:43,347 --> 05:13:44,749
AND THIS WAS DRIVEN BY THREE

6122
05:13:44,749 --> 05:13:46,150
CURIOUS OBSERVATIONS.

6123
05:13:46,150 --> 05:13:48,786
THE FIRST IS AN ANTI-LAG3 ANTIBY

6124
05:13:48,786 --> 05:13:52,423
THAT IF ANY OF YOU DO ANYTHING 3

6125
05:13:52,423 --> 05:13:54,358
BLOCKING ANTIBODY EXPERIMENTS, U

6126
05:13:54,358 --> 05:13:57,361
LIKELY USE WE MADE MANY DECADES

6127
05:13:57,361 --> 05:14:00,965
AGO, DOES NOT BLOCK MHC PLUS 2

6128
05:14:00,965 --> 05:14:01,866
LIGAND INTERACTION.

6129
05:14:01,866 --> 05:14:03,567
RAISING THE QUESTION OF HOW CANT

6130
05:14:03,567 --> 05:14:05,636
WORK IF IT DOESN'T BLOCK THAT

6131
05:14:05,636 --> 05:14:06,938
INTERACTION?

6132
05:14:06,938 --> 05:14:08,639
THE INTERACTION IS BLOCKED BY AL

6133
05:14:08,639 --> 05:14:09,540
THE CLINICAL ANTIBODIES TO THE

6134
05:14:09,540 --> 05:14:11,042
EXTENT WE KNOW.

6135
05:14:11,042 --> 05:14:16,314
THE SECOND POINT IS LAG3 INHIBIY

6136
05:14:16,314 --> 05:14:17,448
ACTIVITY UNLIKE CROSSLINKING, IT

6137
05:14:17,448 --> 05:14:20,418
DOESN'T DRIVE AN INHIBITORY SIG,

6138
05:14:20,418 --> 05:14:21,452
WHICH WAS ALSO CONFUSING IN TERS

6139
05:14:21,452 --> 05:14:24,355
OF THINKING ABOUT HOW IT MIGHT K

6140
05:14:24,355 --> 05:14:24,755
INTRACELLULARLY.

6141
05:14:24,755 --> 05:14:27,158
AND THEN THE THIRD INTERESTING

6142
05:14:27,158 --> 05:14:31,062
THING IS A LONG TIME AGO IN

6143
05:14:31,062 --> 05:14:31,696
HYPERBAKER EXPERIMENTS WE SHOWN

6144
05:14:31,696 --> 05:14:34,098
THAT LAG3 ONLY HAS INHIBITORY

6145
05:14:34,098 --> 05:14:36,067
ACTIVITY IN THE PRESENCE OF

6146
05:14:36,067 --> 05:14:37,568
CORECEPTORS, CD4 AND 8.

6147
05:14:37,568 --> 05:14:39,770
WE SPECULATED EARLY ON THAT MAYE

6148
05:14:39,770 --> 05:14:44,175
THAT IS WHAT LAG3 IS TARGETING

6149
05:14:44,175 --> 05:14:44,508
FUNCTIONALLY.

6150
05:14:44,508 --> 05:14:47,845
THIS IS JUST TO INDICATE THAT TS

6151
05:14:47,845 --> 05:14:50,648
IS THE SIGHT'S PLASMIC DOMAIN OF

6152
05:14:50,648 --> 05:14:52,683
LAG3 AND A PHYLOGENETIC

6153
05:14:52,683 --> 05:14:54,318
RELATIONSHIP TO OTHER SPECIES.

6154
05:14:54,318 --> 05:14:55,586
AND I APPROXIMATE UT THIS UP HEE

6155
05:14:55,586 --> 05:14:57,555
TO KIND OF STILL STRAIGHT TWO

6156
05:14:57,555 --> 05:14:57,788
THINGS.

6157
05:14:57,788 --> 05:15:00,057
THE FIRST IS, THERE ARE NO OBVIS

6158
05:15:00,057 --> 05:15:03,160
MOTIFS THAT MIGHT ASCRIBE FUNCT.

6159
05:15:03,160 --> 05:15:05,863
NO ITEMS OR TYROSINES.

6160
05:15:05,863 --> 05:15:07,365
AND IT WASN'T AS IF WE COULD LOK

6161
05:15:07,365 --> 05:15:08,766
AT THIS THE AND SAY HA HA!

6162
05:15:08,766 --> 05:15:10,868
THIS IS HOW POTENTIALLY IT MIGHT

6163
05:15:10,868 --> 05:15:11,669
WORK.

6164
05:15:11,669 --> 05:15:14,271
THE ONE KEY FEATURE AS YOU CAN E

6165
05:15:14,271 --> 05:15:17,775
HERE, IS AN EXTENSIVE NUMBER OF

6166
05:15:17,775 --> 05:15:18,442
BHUTANIC ACIDS.

6167
05:15:18,442 --> 05:15:20,478
SO LOOKING THROUGH THE LITERATU,

6168
05:15:20,478 --> 05:15:22,480
WE IDENTIFIED A COUPLE OF THOUGS

6169
05:15:22,480 --> 05:15:24,081
THAT DROVE A LOT OF THE PROJECT,

6170
05:15:24,081 --> 05:15:26,083
WHICH I WON'T GO INTO DETAIL IN

6171
05:15:26,083 --> 05:15:29,186
TERMS OF THE DATA BUT SUMMARIZEN

6172
05:15:29,186 --> 05:15:30,588
THE NEXT SLIDE AMOUNT COUPLE OF

6173
05:15:30,588 --> 05:15:31,389
CURIOUS FEATURES.

6174
05:15:31,389 --> 05:15:34,258
THE FIRST IS WITH ALL THE BLEW

6175
05:15:34,258 --> 05:15:36,894
TANNIC ACIDS, THE CYTOPLASMIC

6176
05:15:36,894 --> 05:15:39,597
DOMAIN HAS ACIDIC PI.

6177
05:15:39,597 --> 05:15:45,002
THE PICD1 AND CD8 CYTOPLASMIC

6178
05:15:45,002 --> 05:15:45,970
DOMAINS IS ALSO VERY BASIC AND E

6179
05:15:45,970 --> 05:15:50,107
DID A LOT OF EXPERIMENTS TO SHOW

6180
05:15:50,107 --> 05:15:51,475
THIS SUBSTANTIAL INTERACTIONS

6181
05:15:51,475 --> 05:15:53,477
BETWEEN THOSE TWO SIGHT'S PLASMC

6182
05:15:53,477 --> 05:15:55,679
DOMAINS.

6183
05:15:55,679 --> 05:15:58,849
ELECTROSTATIC INTERACTIONS WHICE

6184
05:15:58,849 --> 05:16:00,885
COULD DUPLICATE IN A SIMPLIFIED

6185
05:16:00,885 --> 05:16:01,185
SYSTEM.

6186
05:16:01,185 --> 05:16:03,587
GIVEN THIS HIGH NUMBER OF ACIDSE

6187
05:16:03,587 --> 05:16:06,624
WONDERED IF IT MIGHT HAVE LOCAL

6188
05:16:06,624 --> 05:16:07,591
PERTURBATION OF THE MEMBRANE WHH

6189
05:16:07,591 --> 05:16:11,595
WE DID SHOW IN A NUMBER OF SUPER

6190
05:16:11,595 --> 05:16:12,329
RESOLUTION MICROSCOPY EXPERIMEN.

6191
05:16:12,329 --> 05:16:15,633
AND THEN THIRDLY, FOUND A RATHER

6192
05:16:15,633 --> 05:16:18,302
OBSCURE STUDY WHICH SUGGESTED TT

6193
05:16:18,302 --> 05:16:24,108
IN THE SAME WAY THAT DICYSTEINSN

6194
05:16:24,108 --> 05:16:27,478
COLLATE METAL IONS, ALTERNATING

6195
05:16:27,478 --> 05:16:28,712
BLEW TANNIC ACIDS COULD DO THAT.

6196
05:16:28,712 --> 05:16:30,514
THE REASON IT WAS OF INTEREST IS

6197
05:16:30,514 --> 05:16:33,117
BECAUSE RATHER UNUSUALLY, THE

6198
05:16:33,117 --> 05:16:35,286
CORECEPTORS INTERACT WITH THE

6199
05:16:35,286 --> 05:16:38,789
DOWNSTREAM KINASE BY THIS

6200
05:16:38,789 --> 05:16:41,158
INTRIGUING DIOCESESTEIN ZINC CLS

6201
05:16:41,158 --> 05:16:43,928
THAT WAS ELUCIDATED BY STEVE

6202
05:16:43,928 --> 05:16:45,329
HARRISON AT HARVARD A NUMBER OF

6203
05:16:45,329 --> 05:16:46,230
YEARS AGO.

6204
05:16:46,230 --> 05:16:48,999
AND SO WE WONDERED WHETHER THISS

6205
05:16:48,999 --> 05:16:50,734
ACTUALLY THE TARGET OF LAG3.

6206
05:16:50,734 --> 05:16:52,203
SO IN THE INTEREST OF TIME, I'M

6207
05:16:52,203 --> 05:16:54,905
GOING TO BASICALLY SUMMARIZE WHT

6208
05:16:54,905 --> 05:16:55,639
THIS PAPER SHOWED.

6209
05:16:55,639 --> 05:16:58,509
AS MANY OF YOU KNOW, THE STANDAD

6210
05:16:58,509 --> 05:17:02,413
MECHANISM OF TCR SIGNALING IS

6211
05:17:02,413 --> 05:17:04,014
ENGAGEMENT WITH PEPTIDE COMPLEXS

6212
05:17:04,014 --> 05:17:06,450
AND BRINGS IN CD4 AND 8 AS WE HA

6213
05:17:06,450 --> 05:17:08,686
NUMBER OF PEOPLE TALK ABOUT.

6214
05:17:08,686 --> 05:17:11,122
LCK BROUGHT CLOSE TO THE T-CELL

6215
05:17:11,122 --> 05:17:13,624
RECEPTOR AND THEN MEDIATES THE Y

6216
05:17:13,624 --> 05:17:16,127
EARLIEST DOWNSTREAM SIGNALING

6217
05:17:16,127 --> 05:17:19,930
EVENTS AND PHOSPHORYLATIONS OF -

6218
05:17:19,930 --> 05:17:21,932
IN THE PRESENCE OF LAG3, WE SHOD

6219
05:17:21,932 --> 05:17:25,402
THAT LAG3 CAN PHYSICALLY INTERAT

6220
05:17:25,402 --> 05:17:27,238
WITH THE T-CELL RECEPTOR BY COIP

6221
05:17:27,238 --> 05:17:29,940
AND SUPER RESOLUTION MICROSCOPY

6222
05:17:29,940 --> 05:17:30,241
APPROACHES.

6223
05:17:30,241 --> 05:17:32,409
THIS PUTS IT INTO CLOSE PROXIMIY

6224
05:17:32,409 --> 05:17:34,612
WITH CD4 AND CD8.

6225
05:17:34,612 --> 05:17:36,847
THESE OPPOSING CHARGES IN THE

6226
05:17:36,847 --> 05:17:40,184
SILENT'S PLASMIC DOMAINS ALLOW R

6227
05:17:40,184 --> 05:17:40,885
ELECTROSTATIC INTERACTIONS AND O

6228
05:17:40,885 --> 05:17:44,288
WE CAN SHOW YOU USING A CASE

6229
05:17:44,288 --> 05:17:46,123
SENSITIVE DYE THAT LOCAL PH OF E

6230
05:17:46,123 --> 05:17:48,726
IMMUNOLOGICAL SYNAPSE IS REDUCEY

6231
05:17:48,726 --> 05:17:51,228
ONE PH, WHICH DOESN'T SEEM VERY

6232
05:17:51,228 --> 05:17:53,130
MUCH, BUT WAS SUFFICIENT AS

6233
05:17:53,130 --> 05:17:55,566
DEMONSTRATED BY SOME NMR

6234
05:17:55,566 --> 05:17:57,234
SPECTROSCOPY EXPERIMENTS, TO WEN

6235
05:17:57,234 --> 05:18:00,237
THE ASSOCIATION OF LCK WITH THE

6236
05:18:00,237 --> 05:18:02,072
CORECEPTOR AND WE COULD SHOW BY

6237
05:18:02,072 --> 05:18:05,242
COIP EXPERIMENTS THAT THAT RESUD

6238
05:18:05,242 --> 05:18:09,747
IN ESSENTIALLY A LOSS OF LCK

6239
05:18:09,747 --> 05:18:14,151
ASSOCIATION WITH THE CORECEPTOR,

6240
05:18:14,151 --> 05:18:14,585
HENCE MIDE QUESTION.

6241
05:18:14,585 --> 05:18:17,354
SO BASICALLY, LAG3 IS NOT AS

6242
05:18:17,354 --> 05:18:18,055
SIGNALING MOLECULE.

6243
05:18:18,055 --> 05:18:20,558
IT'S A SIGNAL DISRUPTOR.

6244
05:18:20,558 --> 05:18:21,792
IT MEDIATES THE INHIBITORY ACTIY

6245
05:18:21,792 --> 05:18:23,761
BY ASSOCIATING WITH THE T-CELL

6246
05:18:23,761 --> 05:18:27,565
RECEPTOR REDUCING CORECEPTOR

6247
05:18:27,565 --> 05:18:30,267
DISASSOCIATION AS A CONSEQUENCEF

6248
05:18:30,267 --> 05:18:33,237
LOWERING THE LOCAL PH BINDING TO

6249
05:18:33,237 --> 05:18:34,572
ZINC AND THEREFORE INHIBITING

6250
05:18:34,572 --> 05:18:36,674
DOWNSTREAM SIGNALING.

6251
05:18:36,674 --> 05:18:38,876
AND YOU COULD ASK THE QUESTION,Y

6252
05:18:38,876 --> 05:18:41,679
HAVE SUCH A COMPLICATED, ODD

6253
05:18:41,679 --> 05:18:42,680
MECHANISM OF ACTION?

6254
05:18:42,680 --> 05:18:45,749
WE THINK THE REASON IS BECAUSE S

6255
05:18:45,749 --> 05:18:48,953
PRO EVOLVED WITH WHAT IS ALSO AN

6256
05:18:48,953 --> 05:18:50,955
UNUSUAL INTERACTION OF CORECEPTR

6257
05:18:50,955 --> 05:18:57,461
WITH LCK BY AS A CONSEQUENCE OF

6258
05:18:57,461 --> 05:18:58,062
THIS DICYSTINE.

6259
05:18:58,062 --> 05:19:02,266
SO THESE TWO MECHANISMS EVOLVED

6260
05:19:02,266 --> 05:19:04,668
TOGETHER AND THEREFORE UNIQUELY

6261
05:19:04,668 --> 05:19:05,002
SPECIFIC.

6262
05:19:05,002 --> 05:19:06,337
THIS OPENS QUESTIONS AS TO WHETR

6263
05:19:06,337 --> 05:19:09,173
OR NOT LAG3 HAS ACTIVITIES IN CS

6264
05:19:09,173 --> 05:19:12,042
THAT DON'T EXPRESS CD4 AND CD8.

6265
05:19:12,042 --> 05:19:13,444
THIS WAS RAISING QUESTIONS AND T

6266
05:19:13,444 --> 05:19:15,846
IS OBVIOUSLY STILL TO BE

6267
05:19:15,846 --> 05:19:16,146
DETERMINED.

6268
05:19:16,146 --> 05:19:19,350
THE OTHER THING I WANT TO TOUCHN

6269
05:19:19,350 --> 05:19:22,453
IS WE KNOW FROM OUR OLD IMMUNOLY

6270
05:19:22,453 --> 05:19:24,288
TEXTBOOKS THAT SIGNAL ONE IS

6271
05:19:24,288 --> 05:19:27,157
DOMINANT AND SIGNAL TWO IS REQUD

6272
05:19:27,157 --> 05:19:30,494
BUT SECONDARILY OF IMPORTANCE IN

6273
05:19:30,494 --> 05:19:31,362
TERMS OF T-CELL ACTIVATION.

6274
05:19:31,362 --> 05:19:33,264
AND WHAT I SHOWED YOU IS THAT L3

6275
05:19:33,264 --> 05:19:36,267
IS REALLY TARGETING SIGNAL ONE D

6276
05:19:36,267 --> 05:19:40,771
SOME BEAUTIFUL WORK FROM OTHERSS

6277
05:19:40,771 --> 05:19:42,973
SHOWN THAT WHILE PD-1 COULD EFFT

6278
05:19:42,973 --> 05:19:45,576
SIGNAL 1 IT HAS A DOMINANT EFFET

6279
05:19:45,576 --> 05:19:46,644
ON CD28.

6280
05:19:46,644 --> 05:19:48,979
SO YOU THINK THE LAG3 SHOULD BEA

6281
05:19:48,979 --> 05:19:51,382
DOMINANT INHIBITORY RECEPTOR OVR

6282
05:19:51,382 --> 05:19:52,883
PD-1 BUT WE CAN SEE THAT'S NOT E

6283
05:19:52,883 --> 05:19:54,485
CASE IN THE CLINIC.

6284
05:19:54,485 --> 05:19:55,386
SO WHY?

6285
05:19:55,386 --> 05:19:56,887
SO ONE POSSIBILITY IS SIMPLY

6286
05:19:56,887 --> 05:19:59,056
BECAUSE PD-1 IS MORE BROADLY

6287
05:19:59,056 --> 05:20:00,658
EXPRESSED AND SO MAYBE THAT'S WY

6288
05:20:00,658 --> 05:20:01,492
IT'S DOMINANT.

6289
05:20:01,492 --> 05:20:03,260
BUT THE ONE THING I'D LIKE TO

6290
05:20:03,260 --> 05:20:05,963
PROPOSE IS MAYBE THE REASON THAT

6291
05:20:05,963 --> 05:20:09,266
LAG3 IS NOT MORE DOMINANT IS

6292
05:20:09,266 --> 05:20:12,369
BECAUSE IT'S RAPIDLY SHED BY

6293
05:20:12,369 --> 05:20:14,371
METALLIC PROTEASES AND THAT PROS

6294
05:20:14,371 --> 05:20:16,173
IS CRITICALLY IMPORTANT IN

6295
05:20:16,173 --> 05:20:17,975
MITIGATING INHIBITORY ACTIVITY.

6296
05:20:17,975 --> 05:20:22,179
WE DID ONE STUDY A NUMBER OF YES

6297
05:20:22,179 --> 05:20:25,983
AGO BY LAWRENCE ANDREWS, TALENTD

6298
05:20:25,983 --> 05:20:29,286
POSTDOC IN THE LAB WHOSE IN THE

6299
05:20:29,286 --> 05:20:30,087
AUDIENCE.

6300
05:20:30,087 --> 05:20:33,991
AND WHAT HE DID WAS TO MAKE A

6301
05:20:33,991 --> 05:20:35,893
NON-SHEDABLE CONDITIONAL KNOCK-N

6302
05:20:35,893 --> 05:20:36,093
MOUSE.

6303
05:20:36,093 --> 05:20:38,395
SO WE COULD BASICALLY IN A CELL

6304
05:20:38,395 --> 05:20:40,197
DEPENDENT MANNER, EXPRESSING

6305
05:20:40,197 --> 05:20:44,601
NON-SHEDABLE LAG3 AND ASK HOW TT

6306
05:20:44,601 --> 05:20:45,169
INFLUENCED T-CELL BIOLOGY.

6307
05:20:45,169 --> 05:20:47,871
AND THIS IS JUST A SLIDE TO

6308
05:20:47,871 --> 05:20:50,074
SUMMARIZE THIS ON WHAT HE SHOWE.

6309
05:20:50,074 --> 05:20:54,511
WHEN T-CELLS EXPRESS A NON-SHEDE

6310
05:20:54,511 --> 05:20:55,979
LAG3, AND EVALUATING IN A MODEL

6311
05:20:55,979 --> 05:20:58,816
THAT IS PD-1 SENSITIVE, THOSE ME

6312
05:20:58,816 --> 05:21:00,784
BECOME THEN PD-1 RESISTANT.

6313
05:21:00,784 --> 05:21:03,687
SO LAG3 BECOMES DOMINANT OVER P1

6314
05:21:03,687 --> 05:21:07,291
AND BLOCKING PD-1 IS INSUFFICIET

6315
05:21:07,291 --> 05:21:09,827
TO DRIVE AN EFFECTIVE ANTI-TUMOR

6316
05:21:09,827 --> 05:21:12,896
IMMUNITY RESPONSE, AT LEAST IN S

6317
05:21:12,896 --> 05:21:13,097
MODEL.

6318
05:21:13,097 --> 05:21:14,598
THIS WAS ALSO SORT OF FOLLOWED P

6319
05:21:14,598 --> 05:21:17,101
WITH SOME HUMAN STUDIES LOOKINGT

6320
05:21:17,101 --> 05:21:19,403
COHORTS OF PATIENTS WITH EITHER

6321
05:21:19,403 --> 05:21:22,806
HEAD AND NECK CANCER OR METASTAC

6322
05:21:22,806 --> 05:21:25,743
MELANOMA AND SHOWED A VERY TIGHT

6323
05:21:25,743 --> 05:21:28,912
INVERSE RELATIONSHIP BETWEEN LA3

6324
05:21:28,912 --> 05:21:32,015
EXPRESSION AND ADAM 10 SO WHEN T

6325
05:21:32,015 --> 05:21:34,918
WAS HIGH, VERY LITTLE LAG3 ON TE

6326
05:21:34,918 --> 05:21:36,420
CELL SURFACE AND VICE VERSA.

6327
05:21:36,420 --> 05:21:38,922
AND ALSO THE PATIENTS THAT HAD H

6328
05:21:38,922 --> 05:21:40,891
ADAM 10 AND THEREFORE LOW LAG3 E

6329
05:21:40,891 --> 05:21:43,494
MUCH MORE RESPONSIVE TO ANTI-PD1

6330
05:21:43,494 --> 05:21:44,762
THAN THE CONVERSE.

6331
05:21:44,762 --> 05:21:47,097
SO PULLING THIS TOGETHER, LAG3

6332
05:21:47,097 --> 05:21:49,600
INHIBITORY ACTIVITY IS TIGHTLY

6333
05:21:49,600 --> 05:21:51,335
REGULATED BY CELL SURFACE SHEDD,

6334
05:21:51,335 --> 05:21:53,504
SOMETHING THAT NEEDS TO BE

6335
05:21:53,504 --> 05:21:54,738
CONSIDERED IN EVALUATING,

6336
05:21:54,738 --> 05:22:00,744
ESPECIALLY IN THE CLINIC LAG3

6337
05:22:00,744 --> 05:22:01,078
THERAPEUTICS.

6338
05:22:01,078 --> 05:22:02,713
NOW TO TALK A LITTLE BIT MORE AT

6339
05:22:02,713 --> 05:22:04,915
THE FUNCTIONAL SIDE OF THINGS.

6340
05:22:04,915 --> 05:22:07,117
WE HAVE BEEN SORT OF LOOKING AT

6341
05:22:07,117 --> 05:22:10,921
THIS IN PARALLEL BOTH IN MOUSE

6342
05:22:10,921 --> 05:22:12,623
STUDIES AND IN CLINICAL TRIALS H

6343
05:22:12,623 --> 05:22:15,459
THE HOPE OF LEARNING █FROM BOTHF

6344
05:22:15,459 --> 05:22:17,628
THESE IN A CROSS DIRECTIONAL

6345
05:22:17,628 --> 05:22:17,861
MANNER.

6346
05:22:17,861 --> 05:22:21,031
I'M GOING TO TALK REALLY JUST AT

6347
05:22:21,031 --> 05:22:23,133
CD8 TODAY BUT WE HAVE ONGOING

6348
05:22:23,133 --> 05:22:25,335
STUDIES TRYING TO LOOK AT THE

6349
05:22:25,335 --> 05:22:28,739
IMPACTS OF LAG3 PD-1 AND THE ENE

6350
05:22:28,739 --> 05:22:30,541
TUMOR MICROENVIRONMENT.

6351
05:22:30,541 --> 05:22:32,743
SO WITH REGARD TO ITS ACTIVITY N

6352
05:22:32,743 --> 05:22:34,845
CD8, WE LOOKED AT THIS IN TWO

6353
05:22:34,845 --> 05:22:37,815
DIFFERENT MODEL SYSTEMS, EITHER

6354
05:22:37,815 --> 05:22:40,050
USING CONDITIONAL FLUXED MOUSE

6355
05:22:40,050 --> 05:22:42,553
MODEL SYSTEMS, WHICH I WON'T TAK

6356
05:22:42,553 --> 05:22:44,955
ABOUT, AND IN PARALLEL, USING

6357
05:22:44,955 --> 05:22:49,126
ADOPTED TRANSFER SYSTEMS OF A TR

6358
05:22:49,126 --> 05:22:50,661
REACTED T-CELL POPULATION, P MA,

6359
05:22:50,661 --> 05:22:52,529
TO RECOGNIZE GP100.

6360
05:22:52,529 --> 05:22:56,200
AND YOU CAN DO THESE EXPERIMENT.

6361
05:22:56,200 --> 05:22:58,635
IF YOU ADOPTIVELY TRANSFER A LAE

6362
05:22:58,635 --> 05:23:02,139
NUMBER OF CELLS, T-CELLS ARE

6363
05:23:02,139 --> 05:23:04,374
SUFFICIENT TO CLEAR GP100

6364
05:23:04,374 --> 05:23:05,409
EXPRESSING B16.

6365
05:23:05,409 --> 05:23:07,744
HOWEVER IF YOU REDUCE THE NUMBEO

6366
05:23:07,744 --> 05:23:09,813
10,000, IT REALLY HAS NO EFFECT

6367
05:23:09,813 --> 05:23:11,748
ALLOWING US TO LOOK AT THE

6368
05:23:11,748 --> 05:23:14,918
CONSEQUENCE OF PD-1 LAG3 OR THE

6369
05:23:14,918 --> 05:23:15,285
COMBO DELETION.

6370
05:23:15,285 --> 05:23:18,522
WHAT YOU CAN SEE HERE IS

6371
05:23:18,522 --> 05:23:20,624
ESSENTIALLY A RECAPITULATION OF

6372
05:23:20,624 --> 05:23:21,725
WHAT YOU WOULD SEE WITH ANTIBODY

6373
05:23:21,725 --> 05:23:24,928
TREATMENT THAT LAG3 ALONE HAS VY

6374
05:23:24,928 --> 05:23:26,330
LITTLE EFFECT.

6375
05:23:26,330 --> 05:23:27,731
PD1 HAS AN EFFECT BUT IT'S ONLY

6376
05:23:27,731 --> 05:23:29,833
WITH A DOUBLE DELETION THAT YOUE

6377
05:23:29,833 --> 05:23:31,635
A BIG REDUCTION IN TUMOR GROWTHD

6378
05:23:31,635 --> 05:23:35,372
YOU CAN SEE THIS BOTH IN THE

6379
05:23:35,372 --> 05:23:37,641
PROPHYLACTIC AND THE THERAPEUTIC

6380
05:23:37,641 --> 05:23:37,875
SETTING.

6381
05:23:37,875 --> 05:23:41,445
THIS ALLOWED US TO INTERROGATE E

6382
05:23:41,445 --> 05:23:43,347
INDIVIDUAL ROLES OF PD-1, LAG3 D

6383
05:23:43,347 --> 05:23:45,249
THE COMBINATION TO SORT OF

6384
05:23:45,249 --> 05:23:47,451
HIGHLIGHT JUST A SNIPIT OF DATA

6385
05:23:47,451 --> 05:23:49,786
FROM WHAT IS A VERY LARGE DATAS.

6386
05:23:49,786 --> 05:23:54,658
ONE OF THE BIGGEST PHENOTYPES IA

6387
05:23:54,658 --> 05:23:56,727
SUBSTANTIAL INCREASE IN T-CELL

6388
05:23:56,727 --> 05:23:57,094
INFILTRATION.

6389
05:23:57,094 --> 05:24:00,063
WHEN YOU DELETE BOTH PD-1 AND L3

6390
05:24:00,063 --> 05:24:01,431
AS INDICATED HERE.

6391
05:24:01,431 --> 05:24:03,534
ONE EXPERIMENTAL APPROACH WE USD

6392
05:24:03,534 --> 05:24:06,069
TO ASK THIS QUESTION IN A

6393
05:24:06,069 --> 05:24:06,970
COMPETITIVE ENVIRONMENT BECAUSEE

6394
05:24:06,970 --> 05:24:09,172
TUMOR IS SMALLER, IS IT THE THE

6395
05:24:09,172 --> 05:24:11,675
TUMOR IS GETTING SMALLER OR CHAE

6396
05:24:11,675 --> 05:24:14,845
IN T-CELL ACTIVITY THAT IS

6397
05:24:14,845 --> 05:24:15,245
INFLUENCING THIS?

6398
05:24:15,245 --> 05:24:17,080
IT'S TO DO A QUADTRANSFER.

6399
05:24:17,080 --> 05:24:19,683
SO THESE ARE CONGENICALLY MARKED

6400
05:24:19,683 --> 05:24:20,951
CELLS THAT WERE TRANSFERRED AT E

6401
05:24:20,951 --> 05:24:23,153
SAME TIME IN EQUAL RATIOS OF 25%

6402
05:24:23,153 --> 05:24:25,956
EACH AND THEN ASK, WHAT IS THE

6403
05:24:25,956 --> 05:24:27,157
REPRESENTATION OF THESE FOUR

6404
05:24:27,157 --> 05:24:29,259
GENOTYPES IN THE TUMOR

6405
05:24:29,259 --> 05:24:29,660
MICROENVIRONMENT?

6406
05:24:29,660 --> 05:24:33,964
WHAT CAN YOU NICELY SEE IS THE

6407
05:24:33,964 --> 05:24:36,366
DELETION OF PD-1 LAG3 RESULTS IA

6408
05:24:36,366 --> 05:24:37,167
SUBSTANTIAL COMPETITIVE ADVANTAE

6409
05:24:37,167 --> 05:24:40,170
OVER THE WILDTYPE CELLS BUT WHAS

6410
05:24:40,170 --> 05:24:43,273
INTERESTING IS THE LAG3 ALONE DS

6411
05:24:43,273 --> 05:24:45,309
HAVE SOME EFFECT IN TERMS OF HAG

6412
05:24:45,309 --> 05:24:46,977
A PHENOTYPE EVEN THOUGH THAT'S

6413
05:24:46,977 --> 05:24:49,146
INSUFFICIENT TO HAVE AN EFFECT N

6414
05:24:49,146 --> 05:24:52,249
THE THERAPEUTIC OUTCOME.

6415
05:24:52,249 --> 05:24:55,385
AND AS EXPECTED, PD-1 ALSO HAS A

6416
05:24:55,385 --> 05:24:57,754
COMPETITIVE ADVANTAGE WHEN DELE.

6417
05:24:57,754 --> 05:24:59,523
IN TERMS OF ADDITIONAL FEATURES

6418
05:24:59,523 --> 05:25:02,259
THAT ARE SPECIFIC TO LAG3, LAG3

6419
05:25:02,259 --> 05:25:06,063
SEEMED TO HAVE A VERY KEY ROLE N

6420
05:25:06,063 --> 05:25:06,863
MODULATING TOX EXPRESSION.

6421
05:25:06,863 --> 05:25:09,166
WHEN YOU DELETE LAG3 ALONE, EVEN

6422
05:25:09,166 --> 05:25:11,668
THOUGH THERE ISN'T MUCH EFFECT N

6423
05:25:11,668 --> 05:25:13,570
TERMS OF INCREASED ANTI-TUMOR

6424
05:25:13,570 --> 05:25:17,674
ACTIVITY, YOU CAN SEE A SUBSTANL

6425
05:25:17,674 --> 05:25:18,475
REDUCTION OF TOX EXPRESSION

6426
05:25:18,475 --> 05:25:20,210
FOLLOWING LAG3 DELETION.

6427
05:25:20,210 --> 05:25:22,479
AND OF COURSE THE GREATEST

6428
05:25:22,479 --> 05:25:24,214
REDUCTION OCCURS WITH THE DOUBLE

6429
05:25:24,214 --> 05:25:24,481
KNOCKOUTS.

6430
05:25:24,481 --> 05:25:30,887
IN TERMS OF PD-1, IT'S DOM

6431
05:25:30,887 --> 05:25:34,291
PERIGNONINANT TYPE WAS INCREASEN

6432
05:25:34,291 --> 05:25:35,192
EFFECTOR ACTIVITY.

6433
05:25:35,192 --> 05:25:36,460
GAMMA INTERFERON PRODUCTION BUTU

6434
05:25:36,460 --> 05:25:39,763
CAN SEE THAT THERE IS A SUBSTANL

6435
05:25:39,763 --> 05:25:42,733
INCREASE WITH THE COMBINATION AS

6436
05:25:42,733 --> 05:25:43,900
INDICATED HERE.

6437
05:25:43,900 --> 05:25:45,469
THIS MADE US ASK THE QUESTION, T

6438
05:25:45,469 --> 05:25:48,872
IS THE ROLE OF GAMMA INTERFERON?

6439
05:25:48,872 --> 05:25:50,774
MOST OF THE FOCUS HAS BEEN

6440
05:25:50,774 --> 05:25:53,110
INFLUENCE OF THE TUMOR

6441
05:25:53,110 --> 05:25:54,077
MICROENVIRONMENT ITSELF BOTH THE

6442
05:25:54,077 --> 05:25:56,713
CELLS AND ALSO THE TUMOR.

6443
05:25:56,713 --> 05:25:59,883
BUT SOME EXTENSIVE SINGLE CELL

6444
05:25:59,883 --> 05:26:01,685
RNA-SEQ AND OTHER STUDIES MADE S

6445
05:26:01,685 --> 05:26:04,087
SUSPICIOUS THE PRIMARY ACTIVITYY

6446
05:26:04,087 --> 05:26:05,989
NOT ACTUALLY BE OTHER CELLS IN E

6447
05:26:05,989 --> 05:26:09,192
TUMOR MICROENVIRONMENT USING OTR

6448
05:26:09,192 --> 05:26:12,596
GENETIC APPROACHES AND ANTIBODY

6449
05:26:12,596 --> 05:26:12,963
BLOCKADE.

6450
05:26:12,963 --> 05:26:15,399
MADE US FOCUS ON THE ROLE OF GAA

6451
05:26:15,399 --> 05:26:17,701
SIGNALING INTRINSICALLY INTO THE

6452
05:26:17,701 --> 05:26:22,806
CD8 AND THE DEFINITIVELY EXPERIT

6453
05:26:22,806 --> 05:26:23,473
BUT -- THAT LAWRENCE AND SMOTHES

6454
05:26:23,473 --> 05:26:28,512
IN THE LAB DID WAS TO DO A CRISR

6455
05:26:28,512 --> 05:26:30,814
MEDIATED -- NOT CRISPR MEDIATED.

6456
05:26:30,814 --> 05:26:33,150
A KNOCK DOWN OF THE GAMMA

6457
05:26:33,150 --> 05:26:35,986
INTERFERON RECEPTOR IN THESE

6458
05:26:35,986 --> 05:26:38,088
ADOPTIVELY TRANSFERRED P MALL

6459
05:26:38,088 --> 05:26:38,455
CELLS.

6460
05:26:38,455 --> 05:26:41,191
SO WE TOOK THE DOUBLE DEFICIENT

6461
05:26:41,191 --> 05:26:43,026
CELLS AND THE WILDTYPES AND KNOD

6462
05:26:43,026 --> 05:26:45,729
DOWN GAMMA INTERFERON RECEPTOR D

6463
05:26:45,729 --> 05:26:47,698
ASKED WHETHER OR NOT THAT IMPACD

6464
05:26:47,698 --> 05:26:50,500
THE ENHANCED ANTI-TUMOR IMMUNITE

6465
05:26:50,500 --> 05:26:50,801
SEEN.

6466
05:26:50,801 --> 05:26:53,203
AS YOU CAN SEE, THAT INCREASED

6467
05:26:53,203 --> 05:26:55,405
ANTI-TUMOR IMMUNITY WAS COMPLETY

6468
05:26:55,405 --> 05:26:58,341
LOST WHEN YOU REMOVED THE GAMMA

6469
05:26:58,341 --> 05:26:59,910
RECEPTOR, SUGGESTING THE KEY ROE

6470
05:26:59,910 --> 05:27:04,681
OF GAMMA IN THIS SETTING WAS CEL

6471
05:27:04,681 --> 05:27:07,350
INTRINSIC RATHER THAN CELL

6472
05:27:07,350 --> 05:27:07,617
EXTRINSIC.

6473
05:27:07,617 --> 05:27:10,654
SO MOVING ON TO THE HUMAN STUDI.

6474
05:27:10,654 --> 05:27:12,756
WE INITIATED THIS IN COLLABORATN

6475
05:27:12,756 --> 05:27:20,664
WITH OUR CLINICAL COLLEAGUES --O

6476
05:27:20,664 --> 05:27:22,165
USED TO BE A RESEARCH ASSISTANT

6477
05:27:22,165 --> 05:27:23,333
PROFESSOR IN THE LAB WHEN WE

6478
05:27:23,333 --> 05:27:24,367
STARTED THESE STUDIES.

6479
05:27:24,367 --> 05:27:26,937
NO YOU SHE HAS HER OWN LAB FOCUG

6480
05:27:26,937 --> 05:27:30,941
ON B CELLS AND TLS.

6481
05:27:30,941 --> 05:27:33,043
WE GOT TOGETHER TO INITIATE A

6482
05:27:33,043 --> 05:27:35,645
BIOMARKER FOCUSED PHASE II CLINL

6483
05:27:35,645 --> 05:27:37,547
TRIAL IN TREATMENT NAIVE.

6484
05:27:37,547 --> 05:27:39,616
SO THESE PATIENTS HADN'T RECEIVD

6485
05:27:39,616 --> 05:27:40,350
ANY OTHER PRIOR TREATMENTS.

6486
05:27:40,350 --> 05:27:43,754
THESE ARE METASTATIC NON RESECTE

6487
05:27:43,754 --> 05:27:44,454
MELANOMA PATIENTS.

6488
05:27:44,454 --> 05:27:51,261
SO IT WAS REALLY AN ENORMOUS AMT

6489
05:27:51,261 --> 05:27:53,063
OF FIRST FROM THE TEAM TO EXTRAT

6490
05:27:53,063 --> 05:27:55,866
THE HIGH QUALITY DATA WITH

6491
05:27:55,866 --> 05:27:57,634
RELATIVELY FEW CORE BIOPSIES WE

6492
05:27:57,634 --> 05:28:01,204
COULD OBTAIN FROM THESE PATIENT.

6493
05:28:01,204 --> 05:28:03,173
WHAT WAS PARTICULARLY UNIQUE ABT

6494
05:28:03,173 --> 05:28:07,577
THIS TRIAL IS IN ADDITION TO A O

6495
05:28:07,577 --> 05:28:09,079
AND COMBO ARM WHICH WOULD BE

6496
05:28:09,079 --> 05:28:12,682
EXPECTED, WE DID GET APPROVAL FA

6497
05:28:12,682 --> 05:28:14,351
LAG3 ONLY ARM, WHICH WAS

6498
05:28:14,351 --> 05:28:15,752
CHALLENGING TO GET THROUGH THE B

6499
05:28:15,752 --> 05:28:19,089
BECAUSE IT HAS NO MONOEFFICACY.

6500
05:28:19,089 --> 05:28:21,958
BUT THEY ALLOWED US TO ENROLL

6501
05:28:21,958 --> 05:28:23,560
PATIENTS AS LONG AS WE RESTRICTD

6502
05:28:23,560 --> 05:28:24,661
TO TWO CYCLES.

6503
05:28:24,661 --> 05:28:28,231
SO PATIENTS WERE ENROLLED.

6504
05:28:28,231 --> 05:28:29,966
THERE WERE TWO BIOPSY AND BLOOD

6505
05:28:29,966 --> 05:28:31,768
DRAW PRIOR TO TREATMENT.

6506
05:28:31,768 --> 05:28:33,570
THEY GET TWO CYCLES TWO WEEKS EH

6507
05:28:33,570 --> 05:28:36,573
AND THEN AFTER 4 WEEKS ALL THE

6508
05:28:36,573 --> 05:28:38,575
PATIENTS GO ON THE DOUBLE LET.

6509
05:28:38,575 --> 05:28:40,243
THAT'S THE BENEFIT TO THE PATIE.

6510
05:28:40,243 --> 05:28:42,479
I'M NOT GOING TO TALK ABOUT DATE

6511
05:28:42,479 --> 05:28:44,681
EVALUATED POST THAT TIME POINT D

6512
05:28:44,681 --> 05:28:48,451
FOCUS JUST ON PRE-POST FOUR-WEEK

6513
05:28:48,451 --> 05:28:48,685
WINDOW.

6514
05:28:48,685 --> 05:28:52,355
WE FOCUSED ON THAT BECAUSE A LOF

6515
05:28:52,355 --> 05:28:54,057
PRIOR STUDIES HAVE SHOWN THAT MH

6516
05:28:54,057 --> 05:28:57,761
OF THE ACTIVITY DOWNSTREAM OF

6517
05:28:57,761 --> 05:28:59,062
ANTI-PD-1 IS EVIDENT WITHIN THE

6518
05:28:59,062 --> 05:29:00,664
FIRST 2-4 WEEKS.

6519
05:29:00,664 --> 05:29:02,465
SO WE FELT CONFIDENT IF THESE

6520
05:29:02,465 --> 05:29:04,601
THINGS WERE GOING TO HAVE SOME

6521
05:29:04,601 --> 05:29:07,370
EFFECT ON THE FUNCTION AND IMMUE

6522
05:29:07,370 --> 05:29:08,471
TRANSCRIPTOME, WE WOULD SEE IT N

6523
05:29:08,471 --> 05:29:10,907
THIS WINDOW.

6524
05:29:10,907 --> 05:29:14,077
AGAIN, WE FOCUSED VERY HEAVILY N

6525
05:29:14,077 --> 05:29:14,978
TRANSCRIPTOMIC APPROACHES.

6526
05:29:14,978 --> 05:29:17,480
WE HAVE DONE SOME SPACIAL ANALYS

6527
05:29:17,480 --> 05:29:18,682
AND FLOW BUT I WON'T TALK ABOUT

6528
05:29:18,682 --> 05:29:20,016
THAT TODAY.

6529
05:29:20,016 --> 05:29:23,086
AND I'M GOING TO FOCUS ON CD8, I

6530
05:29:23,086 --> 05:29:25,155
SAID.

6531
05:29:25,155 --> 05:29:27,290
PARTLY BECAUSE COMPUTATIONAL

6532
05:29:27,290 --> 05:29:28,692
ANALYSIS CLEARLY SHOWED THAT THE

6533
05:29:28,692 --> 05:29:30,660
HIGHEST LEVELS OF PD-1 AND LAG3

6534
05:29:30,660 --> 05:29:35,198
WERE EVIDENT IN CD8s AND WE SAW

6535
05:29:35,198 --> 05:29:37,300
HUGE CHANGES IN OTHER CELL

6536
05:29:37,300 --> 05:29:39,936
POPULATIONS BUT AS I SAID I'M NT

6537
05:29:39,936 --> 05:29:41,905
GOING TO FOCUS ON THAT TODAY.

6538
05:29:41,905 --> 05:29:43,807
SO JUST TO HIGHLIGHT SOME OF THE

6539
05:29:43,807 --> 05:29:44,975
KEY OBSERVATIONS.

6540
05:29:44,975 --> 05:29:46,710
WE USED A WHOLE SERIES OF

6541
05:29:46,710 --> 05:29:47,677
COMPUTATIONS APPROACHES.

6542
05:29:47,677 --> 05:29:50,213
I'M HAPPY TO GO INTO THIS LATER,

6543
05:29:50,213 --> 05:29:52,449
USING BOTH CONVENTIONAL LIGHT AD

6544
05:29:52,449 --> 05:29:55,886
THE BASED CLUSTERING ANALYSIS AD

6545
05:29:55,886 --> 05:29:58,421
ALSO RNA VELOCITY PSEUDOTIME

6546
05:29:58,421 --> 05:30:01,091
ANALYSIS, TO ASK WHAT GENE PROGS

6547
05:30:01,091 --> 05:30:05,595
WERE SELECTIVELY MODULATED BY TE

6548
05:30:05,595 --> 05:30:07,697
IMMUNOTHERAPIES WITH THE NOTION

6549
05:30:07,697 --> 05:30:10,700
THAT WE WOULD AT LEAST AS A FIRT

6550
05:30:10,700 --> 05:30:12,202
MEASURE, EXPECT TO SEE WHAT OTHS

6551
05:30:12,202 --> 05:30:15,605
HAVE SEEN FOLLOWING TREATMENT WH

6552
05:30:15,605 --> 05:30:17,173
PD-1 BLOCKERS.

6553
05:30:17,173 --> 05:30:20,110
SO, ONE OF THE KEY THINGS THAT S

6554
05:30:20,110 --> 05:30:21,912
EXPECTED IS BOTH AN INCREASE TO

6555
05:30:21,912 --> 05:30:25,916
SOME EXTENT, OF EFFECTOR PROGRAS

6556
05:30:25,916 --> 05:30:28,818
AND A REDUCTION OF EXHAUSTION

6557
05:30:28,818 --> 05:30:32,055
SIGNATURES AT LEAST WITH NEVO.

6558
05:30:32,055 --> 05:30:33,623
AS MANY MAY KNOW, THE PRIMARY

6559
05:30:33,623 --> 05:30:38,428
TARGET OF PD-1 IMMUNOTHERAPIES S

6560
05:30:38,428 --> 05:30:39,496
THE PRE EXHAUSTIVE POPULATION TT

6561
05:30:39,496 --> 05:30:41,731
STAN WAS TALKING ABOUT, WITH

6562
05:30:41,731 --> 05:30:42,532
REDUCTION OF EXHAUSTION.

6563
05:30:42,532 --> 05:30:47,003
AND SO, AS EXPECTED, WE SAW THIS

6564
05:30:47,003 --> 05:30:49,172
REDUCTION OF EXHAUSTION PHONOTYE

6565
05:30:49,172 --> 05:30:52,108
WITH AN INCREASED TO SOME EXTENF

6566
05:30:52,108 --> 05:30:53,910
EFFECTOR SIGNATURES BUT WHAT WE

6567
05:30:53,910 --> 05:30:55,912
WERE SURPRISED TO SEE IS A

6568
05:30:55,912 --> 05:30:58,148
SUBSTANTIAL INCREASE IN THE DOUE

6569
05:30:58,148 --> 05:31:02,419
LET BUT SURPRISINGLY A RETENTIOF

6570
05:31:02,419 --> 05:31:04,054
EXHAUSTION SIGNATURES WITH THE

6571
05:31:04,054 --> 05:31:04,354
DOUBLE LET.

6572
05:31:04,354 --> 05:31:06,790
WE DID NOT SEE A REDUCTION OF

6573
05:31:06,790 --> 05:31:08,458
EXHAUSTION SIGNATURES WHICH MIGT

6574
05:31:08,458 --> 05:31:09,826
HAVE BEEN ANTICIPATED.

6575
05:31:09,826 --> 05:31:11,828
AND THE THIS IS THE MOST EVIDENE

6576
05:31:11,828 --> 05:31:14,631
IF WE DO AN X WIDE PLOT, THE

6577
05:31:14,631 --> 05:31:17,233
MAJORITY OF CD8s ARE BOTH

6578
05:31:17,233 --> 05:31:18,902
INCREASING EFFECTOR SIGNATURES,

6579
05:31:18,902 --> 05:31:20,937
BOTH AT THE LEVEL OF GAMMA

6580
05:31:20,937 --> 05:31:23,039
INTERFERON SIGNALING AND TCR

6581
05:31:23,039 --> 05:31:25,608
SIGNALING, BUT RETAINING AN

6582
05:31:25,608 --> 05:31:26,076
EXHAUSTION SIGNATURE.

6583
05:31:26,076 --> 05:31:27,544
THIS WAS CONFUSING BECAUSE WE WD

6584
05:31:27,544 --> 05:31:30,413
EXPECT THIS TO RESULT IN A

6585
05:31:30,413 --> 05:31:31,648
LIMITATION OF ANTI-TUMOR ACTIVIY

6586
05:31:31,648 --> 05:31:34,317
NOT THE ENHANCED ANTI-TUMOR

6587
05:31:34,317 --> 05:31:35,919
ACTIVITY, WHICH IS SEEN IN THE

6588
05:31:35,919 --> 05:31:36,152
CLINIC.

6589
05:31:36,152 --> 05:31:39,255
SO LASTLY, WHAT WE WANTED TO DOS

6590
05:31:39,255 --> 05:31:40,523
UNDERSTAND THE TRANSCRIPTIONAL

6591
05:31:40,523 --> 05:31:41,524
UNDERPINNING OF THIS PROCESS.

6592
05:31:41,524 --> 05:31:45,128
SO WE USED A PROGRAM CALLED SEE

6593
05:31:45,128 --> 05:31:48,965
NICK WHICH INTEGRATES BOTH

6594
05:31:48,965 --> 05:31:50,600
TRANSGRESSION FACTOR MODULATIOND

6595
05:31:50,600 --> 05:31:53,937
THE GENES DOWNSTREAM OF THAT, TE

6596
05:31:53,937 --> 05:31:54,838
REG LON SYSTEM AND WAS SURPRISEO

6597
05:31:54,838 --> 05:31:59,242
SEE NOT ONLY IN REGULATION OF

6598
05:31:59,242 --> 05:32:02,645
TRANSCRIPTION FACTOR FUNCTION, H

6599
05:32:02,645 --> 05:32:06,249
AS BLIMP AND BAT F, BUT ALSO A

6600
05:32:06,249 --> 05:32:09,552
RETENTION AND CENTRAL ROLE FOR

6601
05:32:09,552 --> 05:32:10,553
MAINTENANCE OF TOX EXPRESSION.

6602
05:32:10,553 --> 05:32:13,957
SO YOU MIGHT ASK THE QUESTION, Y

6603
05:32:13,957 --> 05:32:15,458
IS TOX BEING MAINTAINED?

6604
05:32:15,458 --> 05:32:18,628
WHAT I'D LIKE TO KIND OF THROW T

6605
05:32:18,628 --> 05:32:21,364
AS A FEW IDEAS IS THERE HAS BEEA

6606
05:32:21,364 --> 05:32:23,166
NUMBER OF STUDIES WHICH HAVE

6607
05:32:23,166 --> 05:32:26,336
SUGGESTED THAT TOX IS ALSO

6608
05:32:26,336 --> 05:32:29,239
IMPORTANT FOR T-CELL LONGEVITY.

6609
05:32:29,239 --> 05:32:32,942
WE SHOWED THIS IN A STUDY LAST R

6610
05:32:32,942 --> 05:32:36,346
LOOKING AT THE QUESTION OF WHY L

6611
05:32:36,346 --> 05:32:39,049
IMMUNE T-CELLS DO NOT BECOME

6612
05:32:39,049 --> 05:32:41,251
EXHAUSTED EVEN THOUGH THEY RECEE

6613
05:32:41,251 --> 05:32:43,686
CONTINUOUS TCR STIMULATION?

6614
05:32:43,686 --> 05:32:48,058
IN THIS SETTING THEY DO MAINTAIN

6615
05:32:48,058 --> 05:32:50,260
TOX EXPRESSION.

6616
05:32:50,260 --> 05:32:51,127
A LOT OF EXHAUSTION PHENOTYPES D

6617
05:32:51,127 --> 05:32:55,465
YET ARE OBVIOUSLY DRIVING THE

6618
05:32:55,465 --> 05:32:55,765
DISEASE.

6619
05:32:55,765 --> 05:32:58,968
AND ALSO CORATIVELY, YOU MAY REL

6620
05:32:58,968 --> 05:33:01,971
SOMEWHAT CRAZY PAPER THAT DAVE

6621
05:33:01,971 --> 05:33:05,275
PUBLISHED RECENTLY WHERE THEY DA

6622
05:33:05,275 --> 05:33:05,975
10-YEAR SERIAL TRANSFER OF CELLS

6623
05:33:05,975 --> 05:33:07,944
AND SHOWED THAT THESE CELLS GET

6624
05:33:07,944 --> 05:33:10,980
HIGH LEVELS OF TOX EXPRESSION AD

6625
05:33:10,980 --> 05:33:12,749
YET MAINTAIN A MEMORY TYPE.

6626
05:33:12,749 --> 05:33:15,952
SUGGESTING THAT TOX MAY BE

6627
05:33:15,952 --> 05:33:19,055
PREDOMINANTLY DRIVING T-CELL

6628
05:33:19,055 --> 05:33:20,457
LONGEVITY.

6629
05:33:20,457 --> 05:33:21,758
EXHAUSTED CELLS ARE NOT DEAD.

6630
05:33:21,758 --> 05:33:24,561
AND SO IT MAY BE IMPORTANT TO

6631
05:33:24,561 --> 05:33:26,563
MAINTAIN TOX TO ENSURE THAT YOUT

6632
05:33:26,563 --> 05:33:33,470
A DURABLE ANTI-TUMOR RESPONSE.

6633
05:33:33,470 --> 05:33:35,672
LAG3 IS A THIRD CHECKPOINT BECAE

6634
05:33:35,672 --> 05:33:37,874
IT'S THE THIRD ONE TO BE APPROVD

6635
05:33:37,874 --> 05:33:39,976
FOLLOWING PD, APPROXIMATE.

6636
05:33:39,976 --> 05:33:41,778
DL1 AND CTLA4.

6637
05:33:41,778 --> 05:33:44,481
IMPORTANT FOR LAG3 AND THE FIRST

6638
05:33:44,481 --> 05:33:48,985
NEW FDA APPROVAL FOR -- LAG3 ISA

6639
05:33:48,985 --> 05:33:52,755
SIGNAL DISRUPTOR THAT MEDIATES

6640
05:33:52,755 --> 05:33:54,090
ACTIVITY BY ASSOCIATING WITH THE

6641
05:33:54,090 --> 05:33:54,858
T-CELL RECEPTOR.

6642
05:33:54,858 --> 05:33:58,294
I SHOWN YOU A MOUSE MODEL SYSTEM

6643
05:33:58,294 --> 05:34:02,065
WITH THESE MOLECULES COMBINE TO

6644
05:34:02,065 --> 05:34:03,233
ENHANCE T-CELLS PUNCTION.

6645
05:34:03,233 --> 05:34:04,801
WHAT SEEMS TO BE PARTICULARLY

6646
05:34:04,801 --> 05:34:07,170
UNIQUE AND IMPORTANT IS THE CELL

6647
05:34:07,170 --> 05:34:09,172
INTRINSIC ROLE FOR GAMMA INTERFN

6648
05:34:09,172 --> 05:34:11,808
AND THEN LASTLY, IN A PHASE II

6649
05:34:11,808 --> 05:34:13,776
CLINICAL TRIAL, WHAT WAS

6650
05:34:13,776 --> 05:34:15,078
PARTICULARLY SURPRISING IN TERMF

6651
05:34:15,078 --> 05:34:20,283
TWO MESSAGES IS FIRSTLY, ALONE S

6652
05:34:20,283 --> 05:34:21,384
NOT SILENCED.

6653
05:34:21,384 --> 05:34:23,286
IT DOES CREATE HUGE TRANSCRIPTIL

6654
05:34:23,286 --> 05:34:24,287
CHANGES BUT FOR REASONS WE ARE

6655
05:34:24,287 --> 05:34:25,688
STILL TRYING TO UNDERSTAND, THAT

6656
05:34:25,688 --> 05:34:28,191
DOES NOT GIVE RISE TO CLINICAL

6657
05:34:28,191 --> 05:34:28,558
EFFICACY.

6658
05:34:28,558 --> 05:34:30,793
BUT IT RAISES THE POSSIBILITY TT

6659
05:34:30,793 --> 05:34:33,997
COMBINING LAG3 IMMUNOTHERAPIES H

6660
05:34:33,997 --> 05:34:36,266
OTHER THERAPIES MAY BE EFFICACI.

6661
05:34:36,266 --> 05:34:38,601
AND THEN LASTLY, THE COMBO SEEMO

6662
05:34:38,601 --> 05:34:41,905
GIVE RISE TO A COMPLETELY DIFFET

6663
05:34:41,905 --> 05:34:43,806
TRANSCRIPTIONAL AND FUNCTIONAL

6664
05:34:43,806 --> 05:34:45,275
OUTPUT THAT IS NOT EITHER INCRED

6665
05:34:45,275 --> 05:34:48,211
IN TERMS OF WHAT YOU WOULD SEE H

6666
05:34:48,211 --> 05:34:51,381
PD-1 OR ADDITIVE OF THE TWO

6667
05:34:51,381 --> 05:34:52,282
SIGNATURES SEPARATELY.

6668
05:34:52,282 --> 05:34:54,117
SO I'LL STOP THERE AND ACKNOWLEE

6669
05:34:54,117 --> 05:34:56,019
THE PEOPLE THAT CONTRIBUTED TO S

6670
05:34:56,019 --> 05:34:58,321
WORK, PARTICULARLY THE SORT OF

6671
05:34:58,321 --> 05:35:03,226
EARLY STUFF ON LAG3 SIGNALING FM

6672
05:35:03,226 --> 05:35:07,597
CLIFF GUY AND CRAIG WORK MAN, SE

6673
05:35:07,597 --> 05:35:10,099
TERRIFIC MOUSE STUDIES, NON

6674
05:35:10,099 --> 05:35:11,067
CLEAVABLE STUFF FROM LAWRENCE

6675
05:35:11,067 --> 05:35:12,702
ANDREWS AND THEN THE MORE RECENT

6676
05:35:12,702 --> 05:35:15,905
STUFF THAT I SHOWED YOU HERE AND

6677
05:35:15,905 --> 05:35:18,007
THEN TONY DRIVES ALL THE

6678
05:35:18,007 --> 05:35:19,709
COMPUTATIONAL ANALYSIS OF SAMPLS

6679
05:35:19,709 --> 05:35:21,511
FROM PATIENTS AND THEN LAST BUTT

6680
05:35:21,511 --> 05:35:23,112
LEAST, WE WOULDN'T HAVE BEEN ABE

6681
05:35:23,112 --> 05:35:27,617
TO DO THIS WITHOUT OUR CLINICAL

6682
05:35:27,617 --> 05:35:30,153
COLLEAGUES THAT ARE IN THE MEL

6683
05:35:30,153 --> 05:35:31,788
GNOME ALD PROJECTS AND LASTLY,

6684
05:35:31,788 --> 05:35:33,323
PATIENTS AND FAMILIES FOR WILLIG

6685
05:35:33,323 --> 05:35:34,824
TO CONSENT.

6686
05:35:34,824 --> 05:35:36,125
SO I'LL STOP THERE AND HAPPY TO

6687
05:35:36,125 --> 05:35:37,393
TAKE QUESTIONS, THANK YOU.

6688
05:35:37,393 --> 05:35:41,497
[ APPLAUSE ]

6689
05:35:41,497 --> 05:35:41,798
>> THANKS.

6690
05:35:41,798 --> 05:35:45,635
I THINK WE HAVE TIME FOR ONE ORO

6691
05:35:45,635 --> 05:35:52,508
QUESTIONS.

6692
05:35:52,508 --> 05:35:54,410
>> SO THE ANTI-LAG3
ANTIBODIES

6693
05:35:54,410 --> 05:35:57,513
WHICH BLOCKS CD4, BUT WHAT YOU D

6694
05:35:57,513 --> 05:36:00,917
ABOUT MECHANISM IMPLIED THAT THT

6695
05:36:00,917 --> 05:36:02,619
INTERACTION WASN'T CRITICAL, THT

6696
05:36:02,619 --> 05:36:05,421
THERE IS MORE OF A CELL INTRINSC

6697
05:36:05,421 --> 05:36:05,688
MECHANISM.

6698
05:36:05,688 --> 05:36:08,024
HOW WOULD YOU EXPECT THOSE

6699
05:36:08,024 --> 05:36:10,393
ANTIBODIES TO PROVIDE FUNCTION?

6700
05:36:10,393 --> 05:36:11,794
>> SO OBVIOUSLY IN THE
INTERESTF

6701
05:36:11,794 --> 05:36:13,296
TIME I COULDN'T GO INTO THAT IN

6702
05:36:13,296 --> 05:36:14,030
GREAT DETAIL.

6703
05:36:14,030 --> 05:36:17,700
WHAT WE HAVE SHOWN IN THAT NATUE

6704
05:36:17,700 --> 05:36:19,535
IMMUNOLOGY PAPER, IS THAT THE

6705
05:36:19,535 --> 05:36:21,604
ANTIBODY BLOCKS LAG3 ASSOCIATION

6706
05:36:21,604 --> 05:36:22,538
WITH TCR.

6707
05:36:22,538 --> 05:36:26,843
SO IF LAG3 CAN'T -- TCR, IT CANT

6708
05:36:26,843 --> 05:36:27,076
INHIBIT.

6709
05:36:27,076 --> 05:36:28,011
THAT'S PARTICULARLY IMPORTANT.

6710
05:36:28,011 --> 05:36:30,713
BUT WE ALSO THINK THERE MAY BE E

6711
05:36:30,713 --> 05:36:32,382
OTHER ACTIVITIES OF THAT ANTIBOY

6712
05:36:32,382 --> 05:36:34,517
THAT ARE ALSO INDEPENDENT OF THE

6713
05:36:34,517 --> 05:36:37,120
LIGAND WHICH COULD BE IMPORTANT.

6714
05:36:37,120 --> 05:36:39,122
>> SO THIS MAY BE TOO
EXPLORATOY

6715
05:36:39,122 --> 05:36:41,224
FOR THIS SO YOU CAN CUT ME OFF F

6716
05:36:41,224 --> 05:36:42,358
I'M OUT OF LINE.

6717
05:36:42,358 --> 05:36:43,526
I'M INTERESTED IN TWO CONNECTIOS

6718
05:36:43,526 --> 05:36:44,327
OF LAG3.

6719
05:36:44,327 --> 05:36:47,330
ONE IS CD4 THAT IT REMAINS IN TE

6720
05:36:47,330 --> 05:36:48,131
GENOME SO CLOSELY.

6721
05:36:48,131 --> 05:36:50,633
THE OTHER IS WITH THE ASSOCIATIN

6722
05:36:50,633 --> 05:36:54,304
WITH NOTCH WHERE IT HAS THE 10 M

6723
05:36:54,304 --> 05:36:56,339
17 CLEAVAGE OF NOTCH AND

6724
05:36:56,339 --> 05:36:58,708
EXTRACELLULAR DOMAINS -- I'M

6725
05:36:58,708 --> 05:37:02,879
WONDERING AND THEN YOU SHOWED AN

6726
05:37:02,879 --> 05:37:05,214
RVPJ REG LON BEING ENRICHED IN S

6727
05:37:05,214 --> 05:37:06,316
SIGNATURE AT THE END.

6728
05:37:06,316 --> 05:37:07,717
IS IT POSSIBLE THAT THERE ARE KD

6729
05:37:07,717 --> 05:37:10,420
OF LATERAL ASSOCIATIONS OF THE 3

6730
05:37:10,420 --> 05:37:13,122
ON THE T-CELL SURFACE IN SOME OF

6731
05:37:13,122 --> 05:37:15,525
THESE OTHER FAMILY MEMBERS

6732
05:37:15,525 --> 05:37:17,827
POTENTIALLY NOTCH, POTENTIALLY 4

6733
05:37:17,827 --> 05:37:21,831
THAT ARE PROVIDING THE COMPOSITE

6734
05:37:21,831 --> 05:37:23,232
SIGNAL TRANSDUCTION CASCADE?

6735
05:37:23,232 --> 05:37:24,133
>> IT'S A GOOD QUESTION.

6736
05:37:24,133 --> 05:37:26,636
WE HAVEN'T SPECIFICALLY LOOKED T

6737
05:37:26,636 --> 05:37:26,836
THAT.

6738
05:37:26,836 --> 05:37:30,139
YOU MAY RECALL SOME TYPE AGO WED

6739
05:37:30,139 --> 05:37:31,407
A NATURE IMMUNOLOGY PAPER THAT

6740
05:37:31,407 --> 05:37:32,842
TALKED ABOUT THE IMPORTANCE OF

6741
05:37:32,842 --> 05:37:36,946
NOTCH MODULATION DOWNSTREAM OF .

6742
05:37:36,946 --> 05:37:40,149
AND SO THERE MAY WELL BE A TRIFA

6743
05:37:40,149 --> 05:37:46,322
HERE WE JUST HAVEN'T LOOKED INT.

6744
05:37:46,322 --> 05:37:48,925
>> THANK YOU VERY MUCH.

6745
05:37:48,925 --> 05:37:52,128
>> THANK YOU.

6746
05:37:52,128 --> 05:37:59,936
[ APPLAUSE ]

6747
05:37:59,936 --> 05:38:04,741
>> OUR NEXT SPEAKER ALL
THE WAY

6748
05:38:04,741 --> 05:38:08,211
FROM FREDRICK, WHICH IS PART OF

6749
05:38:08,211 --> 05:38:09,545
NCI, IS DANIEL MCVICAR WHO WILL

6750
05:38:09,545 --> 05:38:13,649
TELL US ABOUT A POD 1 MEDIATED -

6751
05:38:13,649 --> 05:38:16,052
I'M NOT EVEN GOING TO TRY --

6752
05:38:16,052 --> 05:38:18,421
>> VERY GOOD.

6753
05:38:18,421 --> 05:38:20,456
THANK YOU VERY MUCH.

6754
05:38:20,456 --> 05:38:22,058
SO THANKS TO THE ORGANIZERS FOR

6755
05:38:22,058 --> 05:38:24,293
GIVING ME AN OPPORTUNITY TO TALA

6756
05:38:24,293 --> 05:38:26,262
LITTLE BIT TO YOU TODAY ABOUT WT

6757
05:38:26,262 --> 05:38:28,731
IS RAPIDLY BECOMING ONE OF OUR

6758
05:38:28,731 --> 05:38:30,767
FAVORITE METABOLITES.

6759
05:38:30,767 --> 05:38:41,344
THIS METABOLITE KNOWN ASIT CONE.

6760
05:38:46,115 --> 05:38:49,051
WE HAD A INTEREST IN THE PERITOL

6761
05:38:49,051 --> 05:38:50,353
CAVITY FOR A NUMBER OF REASONS.

6762
05:38:50,353 --> 05:38:54,290
FROM A CANCER STANDPOINT IT'S VY

6763
05:38:54,290 --> 05:38:56,559
RELEVANT, COLORECTAL AND GYNECOG

6764
05:38:56,559 --> 05:38:59,162
CALL METASTASES, RARELY RECALL

6765
05:38:59,162 --> 05:39:01,931
CANCERS CAN METASTASIZE TO THE

6766
05:39:01,931 --> 05:39:02,198
PARTINIUM.

6767
05:39:02,198 --> 05:39:05,768
THERE ARE A PRIMARY MALIGNANT MS

6768
05:39:05,768 --> 05:39:08,571
THEME OHM AS IN THE PARTINIUM AD

6769
05:39:08,571 --> 05:39:11,574
HGCs OFTEN CAN METASTASIZE AND

6770
05:39:11,574 --> 05:39:12,775
SPREAD IN THE PARTINIUM FOR A VY

6771
05:39:12,775 --> 05:39:13,976
BAD OUTCOME.

6772
05:39:13,976 --> 05:39:15,778
FROM AN IMMUNOLOGIC STANDPOINT W

6773
05:39:15,778 --> 05:39:18,080
THIS IS THE SITE OF UNIQUE

6774
05:39:18,080 --> 05:39:19,682
MACROPHAGE POPULATIONS.

6775
05:39:19,682 --> 05:39:23,319
SO THE RESIDENT MACROPHAGES ARE

6776
05:39:23,319 --> 05:39:24,353
REARRIVED FROM THE YOKE SACK.

6777
05:39:24,353 --> 05:39:27,957
THEY ARE DEPENDENT ON GABA 6

6778
05:39:27,957 --> 05:39:30,059
INDUCED BY RETINOIC ACID.

6779
05:39:30,059 --> 05:39:32,495
AND THEY ARE INVOLVED IN DETECTG

6780
05:39:32,495 --> 05:39:36,599
AND REMOVING MICROORGANISMS FROM

6781
05:39:36,599 --> 05:39:37,500
THE PERITONEAL CAFIT AND

6782
05:39:37,500 --> 05:39:42,305
PARTICIPATE IN WOUND REPAIR.

6783
05:39:42,305 --> 05:39:44,774
THEY ACTUALLY MOVE INTO INJURED

6784
05:39:44,774 --> 05:39:47,376
ORGANS FOR REPAIR.

6785
05:39:47,376 --> 05:39:48,878
FROM THE METABOLIC STANDPOINT WE

6786
05:39:48,878 --> 05:39:53,249
DID A COMPARISON OF PERITONEAL

6787
05:39:53,249 --> 05:39:54,283
FLUID SHOWN HERE WITH SERUM.

6788
05:39:54,283 --> 05:39:56,486
AND THIS WAS PART OF A STUDY WHE

6789
05:39:56,486 --> 05:39:59,088
WE ARE THINKING ABOUT UNIQUE

6790
05:39:59,088 --> 05:40:00,490
METABOLIC NICHES AND CONDITIONS.

6791
05:40:00,490 --> 05:40:02,658
WHAT WE FOUND IS THAT THE

6792
05:40:02,658 --> 05:40:04,393
PERITONEAL SPACE HAD UNIQUE

6793
05:40:04,393 --> 05:40:05,061
METABOLIC MILL YOU.

6794
05:40:05,061 --> 05:40:08,297
IT WAS RICH IN AMINO ACID FUELSD

6795
05:40:08,297 --> 05:40:09,799
RELATIVELY POOR IN LIPID FUELS.

6796
05:40:09,799 --> 05:40:12,335
THIS CONTRASTED TO THE SERUM.

6797
05:40:12,335 --> 05:40:14,504
AND IN THIS PAPER, WE SHOWED THT

6798
05:40:14,504 --> 05:40:16,706
THAT RESIDENT PERITONEAL MACROPE

6799
05:40:16,706 --> 05:40:18,808
POPULATION WAS POISED TO TAKE

6800
05:40:18,808 --> 05:40:21,677
ADVANTAGE OF THAT ENVIRONMENT AD

6801
05:40:21,677 --> 05:40:25,581
PREFERENTIALLY USE THOSE AMINO D

6802
05:40:25,581 --> 05:40:25,915
FUELS.

6803
05:40:25,915 --> 05:40:28,117
SO WE SAID LET'S START TO PERTUB

6804
05:40:28,117 --> 05:40:29,585
THIS ENVIRONMENT WITH TUMOR.

6805
05:40:29,585 --> 05:40:31,521
SO THIS IS THE EXPERIMENTAL SETP

6806
05:40:31,521 --> 05:40:32,788
HE DID A COUPLE OF YEARS AGO.

6807
05:40:32,788 --> 05:40:36,092
WE IMPLANT A TUMOR INTO THE

6808
05:40:36,092 --> 05:40:36,792
PERITONEAL SPACE AND WAIT A COUE

6809
05:40:36,792 --> 05:40:39,495
OF DAYS AND THEN INJECT -- TO CR

6810
05:40:39,495 --> 05:40:41,531
OUT THE RESIDENT MACROPHAGE

6811
05:40:41,531 --> 05:40:41,831
POPULATION.

6812
05:40:41,831 --> 05:40:44,133
AND THEN WE LET IT GO FOR A COUE

6813
05:40:44,133 --> 05:40:44,700
OF DAYS.

6814
05:40:44,700 --> 05:40:48,804
WHAT CAN YOU SEE IS THAT IN ALLF

6815
05:40:48,804 --> 05:40:50,006
THESE CASES, THE CLEARANCE OF TE

6816
05:40:50,006 --> 05:40:52,708
RESIDENT CELLS REDUCES TUMOR

6817
05:40:52,708 --> 05:40:53,209
BURDEN.

6818
05:40:53,209 --> 05:40:55,811
SO IMMUNOLOGISTS MIGHT SAY THOSE

6819
05:40:55,811 --> 05:40:58,514
ARE MYELOID CELLS INHIBITING T-L

6820
05:40:58,514 --> 05:40:58,781
FUNCTION.

6821
05:40:58,781 --> 05:40:59,615
IT'S NOT THAT.

6822
05:40:59,615 --> 05:41:02,952
THESE ARE RESIDENT PERITONEAL ME

6823
05:41:02,952 --> 05:41:07,023
THAT ARE DIRECTLY INFLUENCING TR

6824
05:41:07,023 --> 05:41:07,690
BURDEN IN THE PERITONEAL SPACE.

6825
05:41:07,690 --> 05:41:09,292
AND ALTHOUGH THIS RELATIVELY

6826
05:41:09,292 --> 05:41:10,726
QUICKLY BECAUSE WE PUBLISHED A

6827
05:41:10,726 --> 05:41:12,995
COUPLE OF YEARS AGO, BUT THEN WE

6828
05:41:12,995 --> 05:41:15,097
PULLED THESE RESIDENT MAGS AND

6829
05:41:15,097 --> 05:41:16,299
CHARACTERIZE THEM METABOLICALLY.

6830
05:41:16,299 --> 05:41:19,168
AND WHAT YOU FIND IS THAT RESIDT

6831
05:41:19,168 --> 05:41:21,804
MAGS COME FROM A PERITONEAL SPAE

6832
05:41:21,804 --> 05:41:25,107
AND HAVE VERY HIGH OXIDATIVE RA,

6833
05:41:25,107 --> 05:41:29,412
HIGH BASAL AND HIGH MAXIMUM

6834
05:41:29,412 --> 05:41:30,713
OXIDATIVE RATES T MATTERS WHEREE

6835
05:41:30,713 --> 05:41:31,414
TUMOR IS.

6836
05:41:31,414 --> 05:41:34,250
SO THE BLUE HERE IS AN IP TUMOR.

6837
05:41:34,250 --> 05:41:37,119
THE GREEN IS A SUB TUMOR.

6838
05:41:37,119 --> 05:41:39,422
SO NOT JUST A TUMOR BEARING HOST

6839
05:41:39,422 --> 05:41:43,693
HAS TO BE IN THE PARTINIUM.

6840
05:41:43,693 --> 05:41:46,329
WE DO B16s IT'S EASY.

6841
05:41:46,329 --> 05:41:47,630
THEY ARE EASY TO SEE.

6842
05:41:47,630 --> 05:41:50,032
WE CAN SEE THE SAME EFFECTS WITH

6843
05:41:50,032 --> 05:41:53,636
MORE TRADITIONAL MODELS OF OVARN

6844
05:41:53,636 --> 05:41:53,869
CANCER.

6845
05:41:53,869 --> 05:41:56,238
SO WE WENT ON TO THEN CHARACTERE

6846
05:41:56,238 --> 05:41:58,140
THESE FURTHER T TURNS OUT THAT T

6847
05:41:58,140 --> 05:42:01,444
INCREASE IN METABOLIC ACTIVITY D

6848
05:42:01,444 --> 05:42:03,679
BASAL SPOTS IS INCREASE IN FATTY

6849
05:42:03,679 --> 05:42:04,146
ACID OXIDATION.

6850
05:42:04,146 --> 05:42:05,948
SO YOU CAN KNOCK IT BACK DOWN BY

6851
05:42:05,948 --> 05:42:08,417
TREATING THOSE CELLS AND BRING T

6852
05:42:08,417 --> 05:42:11,354
BACK TO THE CONTROLLED LEVEL.

6853
05:42:11,354 --> 05:42:13,823
WHEN WE DID SOME TARGETED

6854
05:42:13,823 --> 05:42:15,725
METABOLOMICS ON THOSE CELLS, WEW

6855
05:42:15,725 --> 05:42:16,926
SEVERAL THINGS THAT WERE UP

6856
05:42:16,926 --> 05:42:19,829
REGULATED IN TUMOR-BEARING, BUTE

6857
05:42:19,829 --> 05:42:23,132
THAT JUMPED OUT WAS THIS

6858
05:42:23,132 --> 05:42:23,432
METABOLITE.

6859
05:42:23,432 --> 05:42:26,569
IT WAS ABOUT 15-FOLD HIGHER IN E

6860
05:42:26,569 --> 05:42:28,738
RESIDENT MAGS FROM TUMOR-BEARING

6861
05:42:28,738 --> 05:42:29,038
ANIMALS.

6862
05:42:29,038 --> 05:42:33,142
SO YOU MAYBE HEARD ABOUTIT CON8Y

6863
05:42:33,142 --> 05:42:34,343
THIS POINT, ALTHOUGH BACK WHEN E

6864
05:42:34,343 --> 05:42:35,544
WERE DOING THIS, THERE WAS VERY,

6865
05:42:35,544 --> 05:42:36,646
VERY LITTLE OUT THERE.

6866
05:42:36,646 --> 05:42:38,547
SO LET ME TELL YOU ABOUT IT.

6867
05:42:38,547 --> 05:42:41,550
BECAUSE I HOPE TO GET YOU

6868
05:42:41,550 --> 05:42:42,818
INTERESTED THIS AFTERNOON.

6869
05:42:42,818 --> 05:42:46,922
IT'S PROT DUCT OF IMMUNE RESPONE

6870
05:42:46,922 --> 05:42:54,263
GENE 1 OFTEN KNOWN IN THE HUMANS

6871
05:42:54,263 --> 05:42:54,864
A COD 1.

6872
05:42:54,864 --> 05:42:58,167
THOSE OF US THAT ARE VERY OLD TT

6873
05:42:58,167 --> 05:43:00,569
DID MICROARRAYS YEARS AND YEARS

6874
05:43:00,569 --> 05:43:04,340
AGO, IRG1 WAS NEAR THE TOP WHENU

6875
05:43:04,340 --> 05:43:07,576
DID STIMULATED MAGS.

6876
05:43:07,576 --> 05:43:08,144
EVERYONE IGNORED IT.

6877
05:43:08,144 --> 05:43:13,649
SO IT IS A DECARBOXYLASE.

6878
05:43:13,649 --> 05:43:16,152
THE INTERMEDIATE IN THE CONVERSN

6879
05:43:16,152 --> 05:43:18,020
OF CITRATE TO THE ISOCITRATE WIN

6880
05:43:18,020 --> 05:43:20,456
THE TCA.

6881
05:43:20,456 --> 05:43:23,826
SO DECARBOXYLATED -- THE CELESTL

6882
05:43:23,826 --> 05:43:25,361
DESIGN COMMITTEE GAVE US THIS

6883
05:43:25,361 --> 05:43:28,364
LIKELY BECAUSE IT IS A GOOD

6884
05:43:28,364 --> 05:43:29,465
INHIBITORS OF THE GLYOX LATE CYE

6885
05:43:29,465 --> 05:43:32,268
AND WILL BACTERIA.

6886
05:43:32,268 --> 05:43:36,272
THIS IS A BACTERIA THAT THEY INE

6887
05:43:36,272 --> 05:43:38,174
WHEN THEIR CARBON SOURCES ARE

6888
05:43:38,174 --> 05:43:38,407
LIMITED.

6889
05:43:38,407 --> 05:43:40,576
IT ALSO HAS BEEN SHOWN TO BE

6890
05:43:40,576 --> 05:43:43,679
INHIBITOR OF COMPLEX 2 OF THE T.

6891
05:43:43,679 --> 05:43:46,549
AND MANY OF THESE YOU CAN SEE WE

6892
05:43:46,549 --> 05:43:48,350
SHOWN SOMETIME AGO ALTHOUGH THEY

6893
05:43:48,350 --> 05:43:49,685
HAVE BEEN REDISCOVERED MORE

6894
05:43:49,685 --> 05:43:49,952
RECENTLY.

6895
05:43:49,952 --> 05:43:52,021
THERE WAS SOME COMPELLING EVIDEE

6896
05:43:52,021 --> 05:43:54,390
AT THE TIME IT WAS INVOLVED IN N

6897
05:43:54,390 --> 05:43:56,158
DOE TOXIN CLEARS BUT WHAT CAUGHT

6898
05:43:56,158 --> 05:43:59,361
OUR EYE WAS A ZEBRAFISH STUDY TT

6899
05:43:59,361 --> 05:44:04,633
SHOWS THAT IT PROMOTED FATTY ACD

6900
05:44:04,633 --> 05:44:05,968
OXIDATION THROUGH MITOCHONDRIAL

6901
05:44:05,968 --> 05:44:06,569
LOSS.

6902
05:44:06,569 --> 05:44:08,170
WE SAW THIS INCREASE, WE PURSUED

6903
05:44:08,170 --> 05:44:10,973
THIS LINE OF STUDY.

6904
05:44:10,973 --> 05:44:12,808
BUT SO THROUGH THESE MACROPHAGE,

6905
05:44:12,808 --> 05:44:15,277
THEY HAVE IRG MESSAGE AND THEN N

6906
05:44:15,277 --> 05:44:17,179
WE GO IN AND START TO MAKE THAT

6907
05:44:17,179 --> 05:44:19,381
CONNECTION TO FATTY ACID OXIDAT,

6908
05:44:19,381 --> 05:44:20,382
WE CAN USE SI ARE.

6909
05:44:20,382 --> 05:44:21,584
IN.

6910
05:44:21,584 --> 05:44:23,986
As, KNOCK DOWN IRG1 AND KNOCK

6911
05:44:23,986 --> 05:44:25,788
THAT ACTIVITY DOWN.

6912
05:44:25,788 --> 05:44:27,490
IF YOU TREAT YOU KNOCK IT DOWN O

6913
05:44:27,490 --> 05:44:30,926
THE SAME LEVEL SO IT'S THAT FATY

6914
05:44:30,926 --> 05:44:32,328
ACID OXIDATION PART THAT IS

6915
05:44:32,328 --> 05:44:32,595
DEPENDENT.

6916
05:44:32,595 --> 05:44:35,765
AND THAT ALSO IS CONNECTED TO

6917
05:44:35,765 --> 05:44:36,499
GENERAL ROSS LOVES IN THESE CELS

6918
05:44:36,499 --> 05:44:39,001
SO THEY HAVE HIGH ROSS LEVELS

6919
05:44:39,001 --> 05:44:42,805
EXPOSED IN THE TUMOR.

6920
05:44:42,805 --> 05:44:44,206
SO IT ALL LOOKED GOOD.

6921
05:44:44,206 --> 05:44:45,875
AND THE KEY PART IS THAT IF YOU

6922
05:44:45,875 --> 05:44:49,879
KNOCKED DOWN IRG1 YOU CAN ALSO

6923
05:44:49,879 --> 05:44:51,480
REDUCE THE TUMOR BURDEN.

6924
05:44:51,480 --> 05:44:54,583
WE CAN SHOW THAT BY siRNAs AND

6925
05:44:54,583 --> 05:44:57,186
ALSO BY KNOCKING DOWN ALL THE CS

6926
05:44:57,186 --> 05:44:59,789
AND THEN REPLACING THEM WITH

6927
05:44:59,789 --> 05:45:01,590
WILDTYPE CELLS AND THE BURDEN GS

6928
05:45:01,590 --> 05:45:02,491
BACK UP.

6929
05:45:02,491 --> 05:45:04,393
OR REPLACING WITH NULL CELLS AND

6930
05:45:04,393 --> 05:45:05,795
THE BURDEN STAYS LOW.

6931
05:45:05,795 --> 05:45:08,330
I HAVEN'T SHOWN YOU ALL THE DATA

6932
05:45:08,330 --> 05:45:09,698
BECAUSE WE SHOWED IT A COUPLE OF

6933
05:45:09,698 --> 05:45:11,100
YEARS AGO BUT THE GENERAL MODEL

6934
05:45:11,100 --> 05:45:13,402
THAT RESULTED WAS THE TUMORS WEE

6935
05:45:13,402 --> 05:45:16,272
DRIVING EXPRESSION OF IRG1 IN TE

6936
05:45:16,272 --> 05:45:21,510
MACROPHAGE POPULATION AND IT WAS

6937
05:45:21,510 --> 05:45:24,380
DRIVING FATTY ACID MITOCHONDRIAL

6938
05:45:24,380 --> 05:45:25,881
FUEL ROSS IN THE MACROPHAGES WHH

6939
05:45:25,881 --> 05:45:27,183
RESULTED IN INCREASED LEVELS OF

6940
05:45:27,183 --> 05:45:29,018
ROSS SIGNALING IN THE TUMORS.

6941
05:45:29,018 --> 05:45:30,920
WE COULD SHOW THAT BIOCHEMICALLY

6942
05:45:30,920 --> 05:45:32,688
THAT THEY WERE SHOWING EXPOSUREO

6943
05:45:32,688 --> 05:45:34,290
ROSS AND ULTIMATELY THEN THAT

6944
05:45:34,290 --> 05:45:37,493
DRIVES TUMOR BURDEN AND PROMOTES

6945
05:45:37,493 --> 05:45:37,760
ACTIVITY.

6946
05:45:37,760 --> 05:45:40,196
THERE REALLY WAS VERY LITTLE-KNN

6947
05:45:40,196 --> 05:45:41,297
ABOUTIT CON8.

6948
05:45:41,297 --> 05:45:42,698
NOW IT'S VERY, VERY POPULAR.

6949
05:45:42,698 --> 05:45:44,300
THERE IS A VARIETY OF PAPERS THT

6950
05:45:44,300 --> 05:45:47,203
HAVE COME OUT, MANY IN HIGH PROE

6951
05:45:47,203 --> 05:45:50,706
JOURNALS, SHOWING THAT IT CAN DE

6952
05:45:50,706 --> 05:45:53,108
AN EFFECT TRANSCRIPTIONAL

6953
05:45:53,108 --> 05:45:53,409
REGULATION.

6954
05:45:53,409 --> 05:45:54,710
I'M NOT GOING TO GO INTO ALL OF

6955
05:45:54,710 --> 05:45:54,910
THESE.

6956
05:45:54,910 --> 05:45:56,812
I WANT TO GIVE YOU A WORD OF

6957
05:45:56,812 --> 05:45:57,813
CAUTION THAT MAINTENANCE OF THEE

6958
05:45:57,813 --> 05:46:03,419
PAPERS ARE DONE WITH BIOCHEMICAL

6959
05:46:03,419 --> 05:46:05,921
MODIFICATIONS TO THEIT CON8.

6960
05:46:05,921 --> 05:46:09,058
SO EITHER DIMETHYL OR -- [

6961
05:46:09,058 --> 05:46:09,358
INAUDIBLE ]

6962
05:46:09,358 --> 05:46:10,626
WHICH I'LL MENTION IN A MOMENT.

6963
05:46:10,626 --> 05:46:12,628
THESE MODIFICATIONS WERE MADE TO

6964
05:46:12,628 --> 05:46:14,730
FACILITATE GETTING IT INTO THE

6965
05:46:14,730 --> 05:46:17,299
CELLS BUT IT'S NOT REALLY NECESY

6966
05:46:17,299 --> 05:46:19,335
BECAUSE IT GETS IN JUST FINE.

6967
05:46:19,335 --> 05:46:20,603
UNFORTUNATELY, THOSE MOLECULES E

6968
05:46:20,603 --> 05:46:23,038
CHEMISTRY AND BIOLOGY THAT YOU O

6969
05:46:23,038 --> 05:46:27,343
NOT GET FROM NATIVEITA CON8.

6970
05:46:27,343 --> 05:46:29,812
SO PAY ATTENTION TO WHETHER THE

6971
05:46:29,812 --> 05:46:31,614
REAL IS USED OR A DERIVATIVE.

6972
05:46:31,614 --> 05:46:32,715
WE WERE MORE INTERESTED IN SOMEF

6973
05:46:32,715 --> 05:46:34,216
THE ACTIVITIES THAT HAD COME OUA

6974
05:46:34,216 --> 05:46:37,319
LITTLE BIT EARLIER ABOUT THIS.

6975
05:46:37,319 --> 05:46:40,689
IT HAS MULTIPLE METABOLIC FUNCTS

6976
05:46:40,689 --> 05:46:43,626
THAT HAVE BEEN REPORTED.

6977
05:46:43,626 --> 05:46:46,228
INHIBITOR OF FDP PRODUCTION.

6978
05:46:46,228 --> 05:46:48,464
IT CAN INHIBIT SBH.

6979
05:46:48,464 --> 05:46:50,065
COMPELLING DATA WITH INTERFERENE

6980
05:46:50,065 --> 05:46:52,635
WITH VITAMIN B12 SIGNALING.

6981
05:46:52,635 --> 05:46:54,737
WE LIKED THESE LAST TWO ON THE T

6982
05:46:54,737 --> 05:46:56,572
WHICH HAVE BEEN SHOWN TO INHIBIT

6983
05:46:56,572 --> 05:46:57,873
SUBSTRATE LEVEL PHOSPHORYLATIOND

6984
05:46:57,873 --> 05:46:59,842
I'LL SHOW YOU ABOUT THAT IN A

6985
05:46:59,842 --> 05:47:00,075
MOMENT.

6986
05:47:00,075 --> 05:47:02,044
AND OF COURSE AS I MENTIONED, IT

6987
05:47:02,044 --> 05:47:05,147
CAN PROMOTE LIPID UTILIZATION AD

6988
05:47:05,147 --> 05:47:06,548
FATTY ACID OXIDATION.

6989
05:47:06,548 --> 05:47:07,549
BECAUSE THAT WAS AN ACTIVITY THT

6990
05:47:07,549 --> 05:47:09,551
SEEMED TO BE SHOWING UP IN THIS

6991
05:47:09,551 --> 05:47:12,755
TUMOR MODEL AND IN OTHER MODELSF

6992
05:47:12,755 --> 05:47:14,957
FUNCTION, JOHN DECIDED TO ASK TE

6993
05:47:14,957 --> 05:47:15,624
STRAIGHTFORWARD QUESTION OF WHAT

6994
05:47:15,624 --> 05:47:19,161
HAPPENS IF WE THEN STRESS IRG KN

6995
05:47:19,161 --> 05:47:21,263
MICE BY GIVING THEM HIGH-FAT DIS

6996
05:47:21,263 --> 05:47:23,532
AND FORCING THEIR LIVER AND THER

6997
05:47:23,532 --> 05:47:26,268
PHYSIOLOGY TO ADAPT TO THAT

6998
05:47:26,268 --> 05:47:27,036
HIGH-FAT ENVIRONMENT?

6999
05:47:27,036 --> 05:47:30,339
WE THOUGHT THIS WAS A WORTHY

7000
05:47:30,339 --> 05:47:32,074
EXPERIMENT BECAUSE WE HAD SHOWN

7001
05:47:32,074 --> 05:47:35,077
THAT IT CAN BE EXPRESSED IN

7002
05:47:35,077 --> 05:47:38,881
HEPATOCYTES DURING ISCHEMIA AND

7003
05:47:38,881 --> 05:47:39,181
REPERFUSION.

7004
05:47:39,181 --> 05:47:40,249
MAYBE THERE IS A INDICATION ANDT

7005
05:47:40,249 --> 05:47:44,119
WILL SHOW A PHENOTYPE.

7006
05:47:44,119 --> 05:47:48,357
IT DOES.

7007
05:47:48,357 --> 05:47:50,960
WHEN YOU PUT THEM ON HIGH FAT

7008
05:47:50,960 --> 05:47:54,163
DIETS, SERUM FATTY ACID LEVELS E

7009
05:47:54,163 --> 05:47:57,666
UNCHANGED BUT MESENTERIC FAT MAS

7010
05:47:57,666 --> 05:47:59,368
HIGH AND OVER ALL WEIGHT IS HIGH

7011
05:47:59,368 --> 05:48:01,270
AND WHEN YOU LOOK AT THIS UNDERE

7012
05:48:01,270 --> 05:48:02,371
MICROSCOPE, YOU CAN SEE WHY.

7013
05:48:02,371 --> 05:48:03,973
THEY HAVE LOADED TREMENDOUS AMOT

7014
05:48:03,973 --> 05:48:13,983
OF LIPID IN THE IRG NULLS.

7015
05:48:13,983 --> 05:48:15,884
SO, THE IRG MICE ARE LOADING A T

7016
05:48:15,884 --> 05:48:16,585
OF LIPID.

7017
05:48:16,585 --> 05:48:17,553
WHAT IS GOING ON?

7018
05:48:17,553 --> 05:48:19,688
IS IT THE HEPATOCYTES DOING THI?

7019
05:48:19,688 --> 05:48:21,590
WE DON'T THINK IT IS.

7020
05:48:21,590 --> 05:48:24,059
SO HERE WE ARE LOOKING AT THE IG

7021
05:48:24,059 --> 05:48:26,261
MESSAGE LEVELS IN WHOLE LIVER FM

7022
05:48:26,261 --> 05:48:28,397
A WILDTYPE MOUSE ON HIGH FAT DI.

7023
05:48:28,397 --> 05:48:35,337
YOU SEE IT COME UP NICELY.

7024
05:48:35,337 --> 05:48:37,106
ALBUMIN CRE KNOCKOUTS YOU DO.

7025
05:48:37,106 --> 05:48:40,876
IT'S THE IMMUNE SYSTEM NOT THE

7026
05:48:40,876 --> 05:48:41,176
HEPATOCYTES.

7027
05:48:41,176 --> 05:48:43,178
SO IN THE LAB WE WENT BACK TO A

7028
05:48:43,178 --> 05:48:46,181
PUBLISHED DATASET OF SINGLE CELL

7029
05:48:46,181 --> 05:48:48,884
RNA-SEQ OVER THE COURSE OF 36 WS

7030
05:48:48,884 --> 05:48:52,588
OF HIGH FAT DIET AND WHAT HE FOD

7031
05:48:52,588 --> 05:48:54,590
WAS THAT THERE ARE SEVERAL IRG1

7032
05:48:54,590 --> 05:48:56,392
EXPRESSING POPULATIONS IN HERE.

7033
05:48:56,392 --> 05:48:58,927
THESE ARE THE NEUTROPHILS.

7034
05:48:58,927 --> 05:49:01,397
NEUTROPHILS EXPRESS QUITE A BITF

7035
05:49:01,397 --> 05:49:03,599
IRG1 BUT YOU ALSO NOTICE THEY AE

7036
05:49:03,599 --> 05:49:05,200
NOT VERY REACTIVE DURING THE

7037
05:49:05,200 --> 05:49:08,003
HIGH-FAT DIET.

7038
05:49:08,003 --> 05:49:10,672
IN CONTRAST, THESE MACROPHAGES E

7039
05:49:10,672 --> 05:49:12,875
VERY RESPONSIVE TO THE HIGH-FAT

7040
05:49:12,875 --> 05:49:15,477
DIET AND INDUCING A LOT OF IRG1.

7041
05:49:15,477 --> 05:49:17,813
THESE ARE THE INFLAMMATORY

7042
05:49:17,813 --> 05:49:18,680
MACROPHAGES ENTERING THE LIVER

7043
05:49:18,680 --> 05:49:21,150
DURING THE HIGH-FAT DIET.

7044
05:49:21,150 --> 05:49:23,986
SO THAT SUGGESTED IT WAS REALLYE

7045
05:49:23,986 --> 05:49:25,154
MACROPHAGE POPULATION THAT WAS

7046
05:49:25,154 --> 05:49:25,721
DOING IT.

7047
05:49:25,721 --> 05:49:28,791
SO WE COULD THEN GO IN AND SAY,

7048
05:49:28,791 --> 05:49:31,894
OKAY, IS THERE SUFFICIENT LIVERT

7049
05:49:31,894 --> 05:49:34,730
CON8, AND IT SHOWS YOU THE ROUGY

7050
05:49:34,730 --> 05:49:35,898
LEVELS IN ANIMALS PER GRAM.

7051
05:49:35,898 --> 05:49:37,933
HERE IS WILDTYPE MICE AND OF COE

7052
05:49:37,933 --> 05:49:39,701
IN THE KNOCKOUTS ON HIGH-FAT DIT

7053
05:49:39,701 --> 05:49:40,702
THAT IS ABLATED.

7054
05:49:40,702 --> 05:49:44,173
IF WE GIVE A VERY STRONG STIMULS

7055
05:49:44,173 --> 05:49:46,708
TO THE ANIMAL FORIT CON8

7056
05:49:46,708 --> 05:49:48,710
PRODUCTION, YOU CAN SEE THAT NOW

7057
05:49:48,710 --> 05:49:51,413
YOU GET TREMENDOUS LEVELS OFIT 8

7058
05:49:51,413 --> 05:49:54,583
IN THE LIVER.

7059
05:49:54,583 --> 05:49:57,052
ALBUMIN CRE IS INTACT AND THE LE

7060
05:49:57,052 --> 05:49:58,153
IN CRE IS LOW.

7061
05:49:58,153 --> 05:49:59,021
IT'S NOT QUITE ZERO.

7062
05:49:59,021 --> 05:50:00,222
SO THERE IS SOME EVIDENCE THAT

7063
05:50:00,222 --> 05:50:01,824
OTHER POPULATIONS CAN DO IT.

7064
05:50:01,824 --> 05:50:03,826
BUT IN THESE INSTANCES, IT'S THE

7065
05:50:03,826 --> 05:50:05,794
MACROPHAGES THAT ARE DOING IT.

7066
05:50:05,794 --> 05:50:08,730
SO WE WANTED TO KNOW IF THIS MIT

7067
05:50:08,730 --> 05:50:09,331
BE RELEVANT TO HUMAN DISEASE.

7068
05:50:09,331 --> 05:50:12,401
SO WE COLLABORATED WITH THE

7069
05:50:12,401 --> 05:50:15,337
CLINICAL BIOSPECIMEN REPOSITORYD

7070
05:50:15,337 --> 05:50:20,008
WE GOT SAMPLES OF BLOOD AND LIVR

7071
05:50:20,008 --> 05:50:23,912
FROM MASH PATIENTS OR NON-MASH

7072
05:50:23,912 --> 05:50:24,680
CONTROLS.

7073
05:50:24,680 --> 05:50:24,913
-- NASH.

7074
05:50:24,913 --> 05:50:27,216
WHEN YOU START TO LOOK AT THIS

7075
05:50:27,216 --> 05:50:28,750
MECHANISM THEN WHAT CAN YOU SEES

7076
05:50:28,750 --> 05:50:31,720
THAT THEY HAVE HIGH LEVELS OF I1

7077
05:50:31,720 --> 05:50:34,423
AND THOSE LIVERS ARE HIGH FORIT

7078
05:50:34,423 --> 05:50:35,224
CON8 PRODUCTION.

7079
05:50:35,224 --> 05:50:36,325
BUT NOT IN THE BLOOD.

7080
05:50:36,325 --> 05:50:38,727
AND WE HAD SEEN THAT EVEN IN OUR

7081
05:50:38,727 --> 05:50:40,429
HIGH FAT DIET MICE.

7082
05:50:40,429 --> 05:50:42,798
EVEN THOUGH IT ACCUMULATES IN TE

7083
05:50:42,798 --> 05:50:44,133
LIVER T DOES NOT ACCUMULATE OR W

7084
05:50:44,133 --> 05:50:46,168
IN THE PERIPHERAL BLOOD.

7085
05:50:46,168 --> 05:50:49,037
SO, WHAT'S THE RESULT OF THIS LD

7086
05:50:49,037 --> 05:50:49,271
LOADING?

7087
05:50:49,271 --> 05:50:51,039
YOU CAN IMAGINE IT MIGHT BE

7088
05:50:51,039 --> 05:50:52,241
METABOLIC DISORDER AND THAT IS N

7089
05:50:52,241 --> 05:50:53,542
FACT WHAT IT IS.

7090
05:50:53,542 --> 05:50:55,544
THESE MICE DON'T HAVE DIFFERENCS

7091
05:50:55,544 --> 05:50:58,614
IN OVERALL WEIGHT BUT HERE IS TE

7092
05:50:58,614 --> 05:51:00,816
TRACES FROM GLUCOSE TOLERANCE,

7093
05:51:00,816 --> 05:51:01,850
QUANTIFIED OVER HERE.

7094
05:51:01,850 --> 05:51:04,620
THE I ARE RG NULL MICE ON THE HH

7095
05:51:04,620 --> 05:51:07,956
FAT DIETED HAVE WORSE GLUCOSE

7096
05:51:07,956 --> 05:51:08,223
TOLERANCE.

7097
05:51:08,223 --> 05:51:09,458
FOR THAT SORT OF SITUATION, IF I

7098
05:51:09,458 --> 05:51:11,860
CAN FIGURE OUT THIS POINTER, THE

7099
05:51:11,860 --> 05:51:13,862
BLOOD INSULIN LEVELS ARE ALSO

7100
05:51:13,862 --> 05:51:16,365
SUBSTANTIALLY HIGHER IN THE IRG

7101
05:51:16,365 --> 05:51:18,167
NULLS ON WILDTYPE -- SORRY ON

7102
05:51:18,167 --> 05:51:19,334
WESTERN DIETS.

7103
05:51:19,334 --> 05:51:21,937
AND HERE IS INSULIN TOLERANCE TT

7104
05:51:21,937 --> 05:51:24,673
THAT SHOWS THEY HAVE EXACERBATED

7105
05:51:24,673 --> 05:51:29,244
METABOLIC SYNDROME FOR THE IRGs

7106
05:51:29,244 --> 05:51:30,546
IN WESTERN DIET.

7107
05:51:30,546 --> 05:51:31,180
WHY?

7108
05:51:31,180 --> 05:51:32,981
WHY ARE THE LIVERS LOADING WITH

7109
05:51:32,981 --> 05:51:34,383
LIPID AND DRIVING THIS DISEASE?

7110
05:51:34,383 --> 05:51:36,451
SO TO TRY TO GET AT THE MECHANI,

7111
05:51:36,451 --> 05:51:39,154
WE USED ISOLATED HEPATOCYTES INE

7112
05:51:39,154 --> 05:51:40,856
ROW AND THIS SHOWS YOU WHY YOU

7113
05:51:40,856 --> 05:51:45,160
DON'T NEED THOSE MODIFIEDIT CON8

7114
05:51:45,160 --> 05:51:45,460
COMPOUNDS.

7115
05:51:45,460 --> 05:51:48,897
THIS IS THE INTRACELLULAR

7116
05:51:48,897 --> 05:51:50,499
ACCUMULATING AS WE BATHE THE CES

7117
05:51:50,499 --> 05:51:51,266
IN VITRO.

7118
05:51:51,266 --> 05:51:53,869
SO USE THIS AS A MODEL OF EXPOS.

7119
05:51:53,869 --> 05:51:55,837
AND JOHN CAME UP WITH A LIPID

7120
05:51:55,837 --> 05:51:58,273
LOADING ASSAY WHERE WE CAN STAIN

7121
05:51:58,273 --> 05:52:00,175
THE HEPATOCYTES AND SUPPLY THEM

7122
05:52:00,175 --> 05:52:02,144
WITH ACCESS LIPID AND THEY LOADE

7123
05:52:02,144 --> 05:52:04,379
LIPID VERY NICELY BUT IF YOU PRE

7124
05:52:04,379 --> 05:52:06,882
TREAT THEM WITHIT CON8 YOU CAN

7125
05:52:06,882 --> 05:52:08,584
SUPPRESS THAT.

7126
05:52:08,584 --> 05:52:10,152
IT IS DIRECTLY AFFECTING THE

7127
05:52:10,152 --> 05:52:12,354
ABILITY OF THE PEPAS SITES TO

7128
05:52:12,354 --> 05:52:14,289
ACCUMULATE LIPIDS WHEN THE LIPID

7129
05:52:14,289 --> 05:52:15,691
CONCENTRATIONS ARE HIGH.

7130
05:52:15,691 --> 05:52:18,460
IT'S A METABOLIC MECHANISM AS YU

7131
05:52:18,460 --> 05:52:19,294
MIGHT IMAGINE.

7132
05:52:19,294 --> 05:52:21,730
HERE IS ANALYSIS SO NOW WE TREAD

7133
05:52:21,730 --> 05:52:22,864
THEMSELVES EITHER WITH LIPID,IT

7134
05:52:22,864 --> 05:52:24,566
CON8 ALONE OR BOTH HERE AT THE .

7135
05:52:24,566 --> 05:52:27,269
AND WHAT YOU CAN SEE IS WHEN YOU

7136
05:52:27,269 --> 05:52:33,175
TREAT THESE HEPATOCYTES WITHIT

7137
05:52:33,175 --> 05:52:35,377
CONEIGHT BASAL PHOSPHORYLATION S

7138
05:52:35,377 --> 05:52:36,612
UP AND THAT SHOWS WHETHER THEY E

7139
05:52:36,612 --> 05:52:38,580
IN THE PRESENCE OF LIPID OR NOT.

7140
05:52:38,580 --> 05:52:41,883
SO THEIT CON8 IS GEARING UP THER

7141
05:52:41,883 --> 05:52:43,452
METABOLISM AND CAUSING THEM TO N

7142
05:52:43,452 --> 05:52:44,953
MORE LIPID.

7143
05:52:44,953 --> 05:52:49,758
SO INTERESTINGLY BY USING C13 PM

7144
05:52:49,758 --> 05:52:51,426
TRACING, WE DON'T SEE ANY TRACIG

7145
05:52:51,426 --> 05:52:54,997
OF THE OF THE CELLS TO UPITATE

7146
05:52:54,997 --> 05:52:55,197
LIPID.

7147
05:52:55,197 --> 05:52:56,765
WHEN YOU TRACE THE METABOLITES N

7148
05:52:56,765 --> 05:52:59,167
INTO THE TCA CYCLE, YOU SEE A

7149
05:52:59,167 --> 05:53:01,670
GREATER INCORPORATION OF

7150
05:53:01,670 --> 05:53:03,472
LIPID-DERIVED CARBON INTO THE LR

7151
05:53:03,472 --> 05:53:05,374
METABOLITES SHOWING THAT THEY AE

7152
05:53:05,374 --> 05:53:06,975
USING MORE LIPID EVEN THOUGH THE

7153
05:53:06,975 --> 05:53:08,977
RATE OF UPTAKE IS THE SAME AND

7154
05:53:08,977 --> 05:53:09,878
AGAIN THAT WOULD BE CONSISTENT H

7155
05:53:09,878 --> 05:53:12,080
THEM BEING ABLE TO REDUCE THEIR

7156
05:53:12,080 --> 05:53:13,982
OVERALL LIPID BURDEN.

7157
05:53:13,982 --> 05:53:16,485
THE BIOCHEMICAL MECHANISMS FORIT

7158
05:53:16,485 --> 05:53:18,387
CON8 FUNCTION ARE STILL VERY

7159
05:53:18,387 --> 05:53:21,089
CONTROVERSIAL BUT ONE THAT SEEMO

7160
05:53:21,089 --> 05:53:24,192
BE DEVELOPING IN THE LITERATURES

7161
05:53:24,192 --> 05:53:31,099
THE ABILITY OFIT CON8 TO INTERFE

7162
05:53:31,099 --> 05:53:32,267
WITH [ INAUDIBLE ]

7163
05:53:32,267 --> 05:53:34,102
IT'S WHAT CHANGES SUCKS WITHIN E

7164
05:53:34,102 --> 05:53:38,807
TCA CYCLE AND CARRIES OUT

7165
05:53:38,807 --> 05:53:39,174
PHOSPHORYLATION.

7166
05:53:39,174 --> 05:53:41,109
AND IT'S NOW BEEN SHOWN IN VITRO

7167
05:53:41,109 --> 05:53:43,679
THATIT CON8 IS A DIRECT INHIBITR

7168
05:53:43,679 --> 05:53:47,683
OF THIS ENZYME AND THAT IT IS A

7169
05:53:47,683 --> 05:53:55,424
DIRECT SUBSTRATE OF THE TRANSFEE

7170
05:53:55,424 --> 05:53:57,526
WHICH CONVERTS WHILE MOVING IT.

7171
05:53:57,526 --> 05:53:59,394
SO THIS MECHANISM WAS WORKING IN

7172
05:53:59,394 --> 05:54:01,563
OUR CELLS WE SHOULD BE ABLE TO E

7173
05:54:01,563 --> 05:54:02,397
THE FROM TIME TO TIME AND IT LOS

7174
05:54:02,397 --> 05:54:03,198
LIKE WE CAN.

7175
05:54:03,198 --> 05:54:06,702
SO WHEN WE TREAT WITHIT CON8 OR

7176
05:54:06,702 --> 05:54:13,475
LIPID, YOU GET INCREASES IN SUCS

7177
05:54:13,475 --> 05:54:15,110
NO COA AND PERHAPS MOST

7178
05:54:15,110 --> 05:54:17,012
IMPORTANTLY, YOU GET A DEPRESSIN

7179
05:54:17,012 --> 05:54:21,116
IN ATP LEVELS AND INCREASE IN AP

7180
05:54:21,116 --> 05:54:22,617
LEVELS SUGGESTING THESE CELLS AE

7181
05:54:22,617 --> 05:54:25,020
STRUGGLING TO MAINTAIN THEIR

7182
05:54:25,020 --> 05:54:27,723
ENERGETICS AND RAMPING UP THEIR

7183
05:54:27,723 --> 05:54:33,428
METABOLISM TO TRY TO DO THAT.

7184
05:54:33,428 --> 05:54:35,897
MAYBE WE COULD SUPPLYIT CON8 BAK

7185
05:54:35,897 --> 05:54:45,674
AND HERE WE USED ONE OF THE

7186
05:54:45,674 --> 05:54:47,342
DERIVATIVES.

7187
05:54:47,342 --> 05:54:50,812
HERE IS THE HIGH FAT DIET AND TE

7188
05:54:50,812 --> 05:54:53,415
NICE JOB OF KNOCKING DOWN THE LD

7189
05:54:53,415 --> 05:54:53,648
LEVELS.

7190
05:54:53,648 --> 05:54:56,718
HERE IS MANY, MANY MICE

7191
05:54:56,718 --> 05:54:58,720
CHARACTERIZED UP HERE AND YOU CN

7192
05:54:58,720 --> 05:55:04,126
SEE THAT THE 4OI HAS AN EFFECT N

7193
05:55:04,126 --> 05:55:06,328
LIPID DROP WILL THE SIZE AND AR.

7194
05:55:06,328 --> 05:55:08,997
WHEN WE TREAT WITH ROI.

7195
05:55:08,997 --> 05:55:11,032
THE EFFECT ON WILDTYPE MICE IS H

7196
05:55:11,032 --> 05:55:12,334
MORE MODERATE.

7197
05:55:12,334 --> 05:55:13,168
IT DOESN'T REACH SIGNIFICANCE BI

7198
05:55:13,168 --> 05:55:14,736
THINK YOU CAN SEE THAT IS IT TRG

7199
05:55:14,736 --> 05:55:16,538
TO KNOCK IT DOWN A LITTLE BIT.

7200
05:55:16,538 --> 05:55:17,839
PROBABLY NOT SIGNIFICANT BECAUSE

7201
05:55:17,839 --> 05:55:20,442
THEIR LEVELS ARE ALREADY LOWER.

7202
05:55:20,442 --> 05:55:25,747
THE 4OI CORRECTS THE MESENTERICT

7203
05:55:25,747 --> 05:55:29,518
MAS PHENOTYPE AND IT ALSO REVERS

7204
05:55:29,518 --> 05:55:35,257
THOSE METABOLIC DISEASE PARAMET.

7205
05:55:35,257 --> 05:55:36,458
SO I'LL LEAVE WITH YOU THIS WHIH

7206
05:55:36,458 --> 05:55:39,361
IS OUR WORKING MODEL FOR WHAT IS

7207
05:55:39,361 --> 05:55:39,828
HAPPENING.

7208
05:55:39,828 --> 05:55:41,430
SO WE THINK THAT DURING HIGH FAT

7209
05:55:41,430 --> 05:55:44,232
DIET THE RESIDENT MACROPHAGES

7210
05:55:44,232 --> 05:55:46,234
WITHIN THE LIVER ARE BECOMING

7211
05:55:46,234 --> 05:55:46,668
ACTIVATED.

7212
05:55:46,668 --> 05:55:51,640
THEY ARE PRODUCINGITE CONE 8.

7213
05:55:51,640 --> 05:55:54,643
AND WITHIN THE MITOCHONDRIA IT

7214
05:55:54,643 --> 05:55:56,545
INTERFERES WITH SUBSTRATE LEVEL

7215
05:55:56,545 --> 05:55:58,146
PHOSPHORYLATION, DRIVING DOWN TE

7216
05:55:58,146 --> 05:55:59,614
ATP LEVELS AND CAUSING CELLS TO

7217
05:55:59,614 --> 05:56:02,484
RAMP UP THEIR METABOLISM TO TRYO

7218
05:56:02,484 --> 05:56:03,852
PRESERVE THEIR ENERGETICS.

7219
05:56:03,852 --> 05:56:06,154
THE LAST THING I WANT TO LEAVE U

7220
05:56:06,154 --> 05:56:08,457
WITH BECAUSEIT CON8 IS BEING TAD

7221
05:56:08,457 --> 05:56:11,126
ABOUT A LOT AS THIS

7222
05:56:11,126 --> 05:56:12,060
IMMUNOMODULATORY METABOLITE.

7223
05:56:12,060 --> 05:56:13,962
AND ALTHOUGH IT MAY BE IN SOME

7224
05:56:13,962 --> 05:56:16,131
RESPECTS, I REALLY WANT TO KEEPU

7225
05:56:16,131 --> 05:56:16,965
FOCUSED A LITTLE BIT ON WHAT I

7226
05:56:16,965 --> 05:56:19,835
THINK IS REALLY HAPPENING.

7227
05:56:19,835 --> 05:56:21,470
AND THAT THESE CELLS ARE NOT

7228
05:56:21,470 --> 05:56:24,439
SUPPOSED TO BE EXPOSED TOIT CON.

7229
05:56:24,439 --> 05:56:27,943
IT IS WHAT IS GENERATED WHEN A L

7230
05:56:27,943 --> 05:56:28,643
DETECTIVES A BACTERIAL INFECTION

7231
05:56:28,643 --> 05:56:31,279
AND TRIES TO MAINTAIN THAT.

7232
05:56:31,279 --> 05:56:34,349
IT'S THAT ACCESSIT CON8 PRODUCEY

7233
05:56:34,349 --> 05:56:35,884
THE EFFECTOR CELLS THAT IS WORKG

7234
05:56:35,884 --> 05:56:37,953
IN TRANS, AND FORCING THESE OTHR

7235
05:56:37,953 --> 05:56:40,155
CELLS TO DEAL WITH A METABOLITE

7236
05:56:40,155 --> 05:56:41,356
THEY ARE NOT USED TO SEEING AND

7237
05:56:41,356 --> 05:56:44,359
THEY HAVE TO DETOXIFY IT.

7238
05:56:44,359 --> 05:56:48,864
THEY WILL DETOXIFY IT BY LOSING

7239
05:56:48,864 --> 05:56:52,067
THEIR SUBSTRATE LEVEL

7240
05:56:52,067 --> 05:56:52,434
PHOSPHORYLATION.

7241
05:56:52,434 --> 05:56:55,470
THEY'LL LOUIS THEIR SDH ACTIVIT.

7242
05:56:55,470 --> 05:56:59,274
DEPLETION OF KOA AND B12 SO YOUE

7243
05:56:59,274 --> 05:57:01,176
NOT REALLY SUPPOSED TO SEE IT.

7244
05:57:01,176 --> 05:57:02,978
SO DON'T THINK OF IT AS A

7245
05:57:02,978 --> 05:57:03,245
REGULATOR.

7246
05:57:03,245 --> 05:57:04,980
IT'S A TOXIN THAT THE CELLS HAVO

7247
05:57:04,980 --> 05:57:05,380
DEAL WITH.

7248
05:57:05,380 --> 05:57:07,749
SO WITH THAT, I'LL THANK THE PEE

7249
05:57:07,749 --> 05:57:09,451
THAT DID THE WORK.

7250
05:57:09,451 --> 05:57:12,287
THE VAST MAJORITY OF OUR WORK IS

7251
05:57:12,287 --> 05:57:13,755
DONE BY JOHN WISE, SHOWN HERE.

7252
05:57:13,755 --> 05:57:17,459
ALL OF OUR METABOLISM INCLUDINGE

7253
05:57:17,459 --> 05:57:20,028
STORY AND OTHERS IS DONE BY ERIC

7254
05:57:20,028 --> 05:57:20,328
CAPONE HERE.

7255
05:57:20,328 --> 05:57:20,862
THANK YOU VERY MUCH.

7256
05:57:20,862 --> 05:57:28,370
[ APPLAUSE ]

7257
05:57:28,370 --> 05:57:31,573
>> WE DO HAVE TIME FOR A
FEW

7258
05:57:31,573 --> 05:57:38,780
QUESTIONS.

7259
05:57:38,780 --> 05:57:39,481
>> LOVELY TALK.

7260
05:57:39,481 --> 05:57:42,450
JUST A QUICK QUESTION.

7261
05:57:42,450 --> 05:57:45,186
WHEN THE MACROPHAGES ARE SECRET,

7262
05:57:45,186 --> 05:57:47,489
THEY ALSO EXPOSE THEMSELVES TO E

7263
05:57:47,489 --> 05:57:47,789
METABOLITE.

7264
05:57:47,789 --> 05:57:49,891
WHAT HAPPENS THERE?

7265
05:57:49,891 --> 05:57:52,494
DO THEY M1 AND M2 SWITCHING

7266
05:57:52,494 --> 05:57:54,863
PHENOTYPE OR SEPARATION OF CYTOE

7267
05:57:54,863 --> 05:57:55,897
SECRETION OR --

7268
05:57:55,897 --> 05:57:56,298
>> YES.

7269
05:57:56,298 --> 05:57:58,500
SO YOU CAN SEE ALL OF THE

7270
05:57:58,500 --> 05:58:00,735
PARAMETERS THAT I'M SHOWING HERN

7271
05:58:00,735 --> 05:58:02,270
HEPATOCYTES, YOU CAN SEE IN THE

7272
05:58:02,270 --> 05:58:02,470
MAGS.

7273
05:58:02,470 --> 05:58:05,206
SO YOU CAN SEE AS I SHOWED YOU,E

7274
05:58:05,206 --> 05:58:06,908
SAW IT INITIALLY IN THOSE

7275
05:58:06,908 --> 05:58:08,810
MACROPHAGES THAT CAME OUT OF

7276
05:58:08,810 --> 05:58:10,612
TUMOR-BEARING MICE SO THAT HIGH

7277
05:58:10,612 --> 05:58:13,214
BASAL OXIDATIVE PHOSPHORYLATION,

7278
05:58:13,214 --> 05:58:14,916
THAT HIGH UTILIZATION OF FATTY

7279
05:58:14,916 --> 05:58:15,917
ACIDS, THAT'S WITHIN THE

7280
05:58:15,917 --> 05:58:18,086
MACROPHAGES THAT ARE MAKING IT.

7281
05:58:18,086 --> 05:58:20,689
SO JUST THE WAY THEIR INFLUENCIG

7282
05:58:20,689 --> 05:58:22,991
CELLS IN TRANS, THEY ARE SUBJECO

7283
05:58:22,991 --> 05:58:26,995
ALL OF THIS IN CYSAS WELL.

7284
05:58:26,995 --> 05:58:28,897
>> THANK YOU FOR YOUR
TALK.

7285
05:58:28,897 --> 05:58:31,700
I APOLOGIZE IF I MISSED IT.

7286
05:58:31,700 --> 05:58:35,103
BUT M1 AND M2 MACROPHAGES HAVE

7287
05:58:35,103 --> 05:58:36,438
DIFFERENTIAL METABOLISM.

7288
05:58:36,438 --> 05:58:37,939
IS A HETEROGENOUS POPULATION YOU

7289
05:58:37,939 --> 05:58:39,507
WERE STUDYING?

7290
05:58:39,507 --> 05:58:41,042
>> SO IN THE RESIDENT
COMPARTME,

7291
05:58:41,042 --> 05:58:44,212
IT DOESN'T REALLY FALL INTO A CN

7292
05:58:44,212 --> 05:58:45,013
M1 AND M2.

7293
05:58:45,013 --> 05:58:48,016
SO YOU PROBABLY SEEN PEOPLE THAT

7294
05:58:48,016 --> 05:58:51,753
WILL KIND OF TELL THESE STORIES

7295
05:58:51,753 --> 05:58:53,622
MORE FARINGLY AND SAY IF YOU TAE

7296
05:58:53,622 --> 05:58:56,424
OUT THE RESIDENT MAGS, THEY'LL E

7297
05:58:56,424 --> 05:58:58,226
SOME M1 GENES BUT IF YOU LOOK FR

7298
05:58:58,226 --> 05:59:00,228
THE M2 GENES THEY'LL HAVE THOSE

7299
05:59:00,228 --> 05:59:02,297
TOO.

7300
05:59:02,297 --> 05:59:04,199
IT'S NOT CLEAR-CUT.

7301
05:59:04,199 --> 05:59:05,800
THIS EFFECT SEEMS TO BE MOSTLY D

7302
05:59:05,800 --> 05:59:07,802
TO THIS M1 RESPONSE WHICH DRIVEA

7303
05:59:07,802 --> 05:59:10,405
LOT OFIT CON8.

7304
05:59:10,405 --> 05:59:12,741
A LAB SHOWED THAT THERE CAN BE

7305
05:59:12,741 --> 05:59:18,913
DIRECT INHIBITION OF M2 DEVELOPT

7306
05:59:18,913 --> 05:59:19,180
BYIT CON8.

7307
05:59:19,180 --> 05:59:21,449
SOME OF THAT IS DONE WITH THE

7308
05:59:21,449 --> 05:59:22,117
MODIFIED METAP LIGHTS.

7309
05:59:22,117 --> 05:59:23,718
SO YOU SHOULD TAKE A LOOK AT IT.

7310
05:59:23,718 --> 05:59:25,420
BUT IT'S POSSIBLE THAT NOT ONLYS

7311
05:59:25,420 --> 05:59:27,322
IT MOSTLY ASSOCIATED WITH ONE BT

7312
05:59:27,322 --> 05:59:32,527
IT'S AN ACTIVE REPRESSOR OF 2.

7313
05:59:32,527 --> 05:59:35,530
>> VERY COOL TALK.

7314
05:59:35,530 --> 05:59:40,335
I KNOW THATIT CON8 IS OR CAN BE

7315
05:59:40,335 --> 05:59:42,437
DEGRADED BY CERTAIN MICROBES.

7316
05:59:42,437 --> 05:59:44,139
I DON'T KNOW IF YOU LOOKED INTOE

7317
05:59:44,139 --> 05:59:47,342
ROLE OF WIDE RANGING IF IT'S

7318
05:59:47,342 --> 05:59:50,045
VARIABLE -- SPREAD THROUGHOUT TE

7319
05:59:50,045 --> 05:59:51,346
GUT TO THE PARTINIUM OR SOMETHIG

7320
05:59:51,346 --> 05:59:52,547
LIKE THAT --

7321
05:59:52,547 --> 05:59:53,682
>> YES.

7322
05:59:53,682 --> 05:59:54,949
SO VERY GOOD POINTS.

7323
05:59:54,949 --> 05:59:55,283
YOU'RE RIGHT.

7324
05:59:55,283 --> 05:59:57,052
WHAT HE'S REFERRING TO IS IN THE

7325
05:59:57,052 --> 05:59:59,154
BATTLE THAT IS GOING ON WHERE A

7326
05:59:59,154 --> 06:00:01,856
MACROPHAGE WILL EAT A BUG, THE G

7327
06:00:01,856 --> 06:00:04,926
CHANGES THE METABOLISM TO SURVIE

7328
06:00:04,926 --> 06:00:08,163
AND THE BUG MAKESIT CON8 TO POIN

7329
06:00:08,163 --> 06:00:10,131
THAT.

7330
06:00:10,131 --> 06:00:11,933
MANY MICROORGANISMS CAN

7331
06:00:11,933 --> 06:00:12,934
METABOLIZEIT CON8.

7332
06:00:12,934 --> 06:00:15,236
WE LOOKED AT THE MICROBIOTA IN E

7333
06:00:15,236 --> 06:00:16,671
RESTING STATE.

7334
06:00:16,671 --> 06:00:19,741
WE SEE LITTLE IF ANY CHANGE THE.

7335
06:00:19,741 --> 06:00:22,343
WHETHER SOMETHING MAY BE HAPPENG

7336
06:00:22,343 --> 06:00:24,179
IN HIGH FAT DIET, WE DON'T KNOW.

7337
06:00:24,179 --> 06:00:28,049
WE HAVE TO LOOK.

7338
06:00:28,049 --> 06:00:30,251
OVER ALL, I THINK THAT THERE ISA

7339
06:00:30,251 --> 06:00:32,454
GOOD LIKELIHOOD THAT SOME OF THE

7340
06:00:32,454 --> 06:00:35,290
BACTERIAL SPECIES ARE CHANGING,

7341
06:00:35,290 --> 06:00:36,558
HOWEVER, IT'S DIFFICULT TO DO

7342
06:00:36,558 --> 06:00:38,259
BECAUSE YOU CAN GO IN AND YOU CN

7343
06:00:38,259 --> 06:00:40,528
DO THESE EXPERIMENTS WHERE YOU

7344
06:00:40,528 --> 06:00:43,765
TITRATE INIT CON8 INTO A GIVEN

7345
06:00:43,765 --> 06:00:45,633
BACTERIAL STRAIN AND THEN SUPPRS

7346
06:00:45,633 --> 06:00:48,169
IT AND NOW IT FEEDS ON IT.

7347
06:00:48,169 --> 06:00:49,838
SO I'M NOT SURE IF WE'RE GOING O

7348
06:00:49,838 --> 06:00:51,873
SEE IT PROMOTE SPECIES.

7349
06:00:51,873 --> 06:00:53,842
WE ARE JUST TRYING TO SORT THAT

7350
06:00:53,842 --> 06:00:56,144
OUT.

7351
06:00:56,144 --> 06:00:56,544
>> GREAT POINT.

7352
06:00:56,544 --> 06:00:58,046
THANK YOU.

7353
06:00:58,046 --> 06:00:58,813
>> ALWAYS A PLEASURE.

7354
06:00:58,813 --> 06:01:00,749
IT WAS REALLY GREAT, THANK YOU.

7355
06:01:00,749 --> 06:01:03,952
SO THERE IS A LOT OF STUFF ON TE

7356
06:01:03,952 --> 06:01:04,853
ALPHA SUCKS NAT RATIO IN TERMS F

7357
06:01:04,853 --> 06:01:07,355
BEING A MARKER OF DIFFERENTIATI.

7358
06:01:07,355 --> 06:01:10,425
IN YOUR CONTEXT WHERE YOU MIGHTE

7359
06:01:10,425 --> 06:01:12,060
CHANGING SUCKS INHALATION BECAUE

7360
06:01:12,060 --> 06:01:14,662
OF YOURIT CON8 LEVELS.

7361
06:01:14,662 --> 06:01:17,165
SO ONE IS, DO YOU KNOW IF THEREE

7362
06:01:17,165 --> 06:01:18,366
DIFFERENCES IN SUCKS INHALATIOND

7363
06:01:18,366 --> 06:01:20,969
IN YOUR IRG KNOCKOUT AND CAN YOU

7364
06:01:20,969 --> 06:01:25,373
PLAY AROUND WITH IT AS A RATIO F

7365
06:01:25,373 --> 06:01:25,673
SUCKSINATE?

7366
06:01:25,673 --> 06:01:28,209
>> SO WE HAVEN'T LOOKED
DIRECTLT

7367
06:01:28,209 --> 06:01:29,878
PROTEIN SUCKS INHALATION.

7368
06:01:29,878 --> 06:01:30,912
THE RATIOS ARE DEFINITELY CHANGG

7369
06:01:30,912 --> 06:01:34,482
IN THE SENSE THAT IF YOU DO BROD

7370
06:01:34,482 --> 06:01:35,450
METABOLOMICS ON CELLS EXPRESSINA

7371
06:01:35,450 --> 06:01:37,786
LOT OFIT CON8 VERSUS THOSE THAT

7372
06:01:37,786 --> 06:01:39,387
AREN'T, ONE OF THE FEW THINGS TT

7373
06:01:39,387 --> 06:01:42,891
SHOWS UP IS THE ACCUMULATION OF

7374
06:01:42,891 --> 06:01:43,892
SUCKSINATE THAT NORMALLY OCCURS

7375
06:01:43,892 --> 06:01:46,161
DURING ACTIVATION IS GONE IN THE

7376
06:01:46,161 --> 06:01:47,562
ABSENCE OFIT CON8.

7377
06:01:47,562 --> 06:01:49,264
THERE IS ONE OF THE MODELS THATS

7378
06:01:49,264 --> 06:01:50,965
BEEN PUT OUT FOR THE

7379
06:01:50,965 --> 06:01:53,768
ANTI-INFLAMMATORY ACTIVITY IS

7380
06:01:53,768 --> 06:01:54,569
INTERFERENCE WITH TET 2.

7381
06:01:54,569 --> 06:01:58,373
WHICH IS A SUCKSINATE APP INDICD

7382
06:01:58,373 --> 06:01:59,374
GLUTEERATE-DEPENDENT ENZYME.

7383
06:01:59,374 --> 06:02:02,177
WHAT THEY THINK IS HAPPENING THE

7384
06:02:02,177 --> 06:02:04,078
IS DIRECT COMPETITION FOR THE

7385
06:02:04,078 --> 06:02:06,381
BINDING SITES ON THE ENZYME BYIT

7386
06:02:06,381 --> 06:02:10,685
CON8 BECAUSE IT'S SO SIMILAR TO

7387
06:02:10,685 --> 06:02:11,286
ALPHA GLUTE RATE.

7388
06:02:11,286 --> 06:02:14,189
IT'S NOT EVEN THE RATIO, IT'S A

7389
06:02:14,189 --> 06:02:16,391
DIRECT INHIBITION.

7390
06:02:16,391 --> 06:02:19,227
THAT'S WHAT THEY SUGGEST.

7391
06:02:19,227 --> 06:02:19,761
THANK YOU.

7392
06:02:19,761 --> 06:02:29,971
[ APPLAUSE ]

7393
06:02:43,451 --> 06:02:45,987
>> GREGOIRE ALTAN-BONNET
WILL GO

7394
06:02:45,987 --> 06:02:47,889
FIRST AND THE DR. TAYLOR WILL GO

7395
06:02:47,889 --> 06:02:49,290
SECOND AND WE'LL TAKE QUESTIONS

7396
06:02:49,290 --> 06:02:54,395
AFTER THEY ARE BOTH DONE SPEAKI.

7397
06:02:54,395 --> 06:03:00,501
>> WE ARE VERY EXCITED
ABOUT THE

7398
06:03:00,501 --> 06:03:01,302
LAST TALKS.

7399
06:03:01,302 --> 06:03:05,974
-- REALLY NICE TO BE ABLE TO MOL

7400
06:03:05,974 --> 06:03:09,143
T-CELL ACTIVATION AND USE THAT O

7401
06:03:09,143 --> 06:03:19,487
MAKE BETTER DESIGNS.

7402
06:03:23,391 --> 06:03:25,793
I'M GOING TO STOP WITH THE 3

7403
06:03:25,793 --> 06:03:27,228
MUSKETEERS WHO DID MOST OF THE

7404
06:03:27,228 --> 06:03:27,528
WORK.

7405
06:03:27,528 --> 06:03:38,139
SO A TIGHT COLLABORATION WITH TE

7406
06:03:41,843 --> 06:03:41,976
LABS.

7407
06:03:41,976 --> 06:03:42,310
[ INAUDIBLE ]

7408
06:03:42,310 --> 06:03:45,747
DOING A LOT OF THE WORK AND MY B

7409
06:03:45,747 --> 06:03:50,351
HAS BEEN DEVELOPING A LOT.

7410
06:03:50,351 --> 06:03:55,924
VERY TIGHT INTEGRATION OF SYSTES

7411
06:03:55,924 --> 06:04:02,931
ENERGY AND COLLABORATION -- [

7412
06:04:02,931 --> 06:04:03,231
INAUDIBLE ]

7413
06:04:03,231 --> 06:04:06,034
SO WE ARE INTERESTED IN MODEL

7414
06:04:06,034 --> 06:04:08,036
CANCER -- CAN COLLECT THE BLOOD

7415
06:04:08,036 --> 06:04:11,439
FROM THE PATIENTS AND COLLECT SE

7416
06:04:11,439 --> 06:04:13,141
LEUKOCYTE FROM TUMORS AND TRY TO

7417
06:04:13,141 --> 06:04:18,346
EXPAND THEM AND MODIFY THEM AS E

7418
06:04:18,346 --> 06:04:24,352
DRUG -- THE IDEA IS TO DEVELOP A

7419
06:04:24,352 --> 06:04:27,922
GOOD POPULATION OF T-CELL IN CA.

7420
06:04:27,922 --> 06:04:31,960
WE CAN -- WE MUST BE AWARE OF TE

7421
06:04:31,960 --> 06:04:40,034
THINGS AND SOME SUCCESS AND

7422
06:04:40,034 --> 06:04:42,070
CONTEXT -- IN WOB CLINICAL TRIA-

7423
06:04:42,070 --> 06:04:44,038
SO WE ARE VERY INTERESTED IN BEG

7424
06:04:44,038 --> 06:04:47,742
ABLE TO CHARACTERIZE TO REALLY

7425
06:04:47,742 --> 06:04:48,943
UNDERSTAND WHAT DRIVES RESPONSE

7426
06:04:48,943 --> 06:04:50,144
AGAINST CANCER.

7427
06:04:50,144 --> 06:04:52,146
AND TO DEVELOP THAT, I'M GOING O

7428
06:04:52,146 --> 06:04:53,047
GO QUICKLY.

7429
06:04:53,047 --> 06:04:57,852
WE DEVELOPED A PLATFORM WHICH I-

7430
06:04:57,852 --> 06:05:02,357
IT'S GEARED FOR -- ROBOTIC PLATM

7431
06:05:02,357 --> 06:05:03,758
EXPERIMENTS AUTOMATICALLY.

7432
06:05:03,758 --> 06:05:13,768
WHAT THIS PLATFORM DOES COLLECT

7433
06:05:13,768 --> 06:05:17,839
TUMOR MODELS AND LOAD IT UP AND

7434
06:05:17,839 --> 06:05:20,742
REALLY GO AND COLLECT THE TIME

7435
06:05:20,742 --> 06:05:25,880
POINTS AND LOOK AT THE CYTOKINE,

7436
06:05:25,880 --> 06:05:28,649
COLLECT THE CELLS TO CHARACTERIE

7437
06:05:28,649 --> 06:05:28,850
THEM.

7438
06:05:28,850 --> 06:05:36,958
I'M SHOWING YOU A -- T-CELLS ANB

7439
06:05:36,958 --> 06:05:38,760
CELLS RESPONDING TO A MOUSE MODL

7440
06:05:38,760 --> 06:05:41,062
WE USED TO BUILD THE MODEL.

7441
06:05:41,062 --> 06:05:44,365
SO I WOULD LOVE TO SHOW YOU A LE

7442
06:05:44,365 --> 06:05:45,333
VIDEO BUT IT NEVER WORKS SO I'M

7443
06:05:45,333 --> 06:05:47,068
GOING TO SHOW YOU A VIDEO OF WHT

7444
06:05:47,068 --> 06:05:48,669
THE ROBOT LOOKS LIKE.

7445
06:05:48,669 --> 06:05:50,638
IT DOES EXACTLY WHAT WE WILL BE

7446
06:05:50,638 --> 06:05:53,941
DOING IN THE LAB AT THE BENCH.

7447
06:05:53,941 --> 06:05:54,642
COLLECTS PLATE FROM THE INCUBAT,

7448
06:05:54,642 --> 06:05:59,147
GRAB IT, REMOVE IT.

7449
06:05:59,147 --> 06:06:01,783
YOU CAN PROGRAM IT AND OF COURSE

7450
06:06:01,783 --> 06:06:04,085
IT'S STILL GOING TO KEEP WORKING

7451
06:06:04,085 --> 06:06:06,988
WHILE YOU GUYS WILL BE AT HOME.

7452
06:06:06,988 --> 06:06:12,260
AND WE HAVE DONE A LOT OF WORK O

7453
06:06:12,260 --> 06:06:16,297
DEVELOP -- [ INAUDIBLE ]

7454
06:06:16,297 --> 06:06:20,535
WE HAVE A WAY TO COLLECT QUICKLO

7455
06:06:20,535 --> 06:06:22,270
USE FOR MACHINE LEARNING.

7456
06:06:22,270 --> 06:06:24,505
SO STRONGLY RECOMMEND YOU CHECKT

7457
06:06:24,505 --> 06:06:25,573
THE PAPER LAST YEAR.

7458
06:06:25,573 --> 06:06:28,376
IT'S REALLY A GOOD WAY TO RUN AT

7459
06:06:28,376 --> 06:06:32,280
OF IMAGES VERY QUICKLY ON A FEW

7460
06:06:32,280 --> 06:06:32,513
SAMPLES.

7461
06:06:32,513 --> 06:06:35,483
WE CAN UPDATE THAT.

7462
06:06:35,483 --> 06:06:39,487
SO THIS IS -- TEST RUN TO CHECKE

7463
06:06:39,487 --> 06:06:47,595
PLATFORM WAS WORKING.

7464
06:06:47,595 --> 06:06:50,098
WE -- SIX HEALTHY DONORS.

7465
06:06:50,098 --> 06:06:52,800
I'M SHOWING THAT TO GIVE YOU A

7466
06:06:52,800 --> 06:06:54,969
SENSE OF THE RICHNESS.

7467
06:06:54,969 --> 06:06:59,574
THESE ARE OVER THREE DAYS AND WE

7468
06:06:59,574 --> 06:07:10,284
ARE JUST GOING -- RATIOS AND D 

7469
06:07:12,253 --> 06:07:13,488
DONORS -- MULTIPLY CONDITIONS.

7470
06:07:13,488 --> 06:07:14,722
VERY INTERESTING TO MODEL.

7471
06:07:14,722 --> 06:07:25,299
WE CAN REALLY USE THAT TO -- VEY

7472
06:07:25,299 --> 06:07:28,302
RICH AND WE WANTED TO USE THAT O

7473
06:07:28,302 --> 06:07:30,972
REALLY BUILD MODELS TO UNDERSTAD

7474
06:07:30,972 --> 06:07:35,109
THE WAY WE CAN TWEAK TO MAKE THM

7475
06:07:35,109 --> 06:07:35,343
BETTER.

7476
06:07:35,343 --> 06:07:38,112
AND IT GOES BACK TO VERY OLD

7477
06:07:38,112 --> 06:07:39,614
PROGRAM I HAVE BEEN INTERESTED N

7478
06:07:39,614 --> 06:07:41,315
IN MANY CONTEXT OVER THE YEARS

7479
06:07:41,315 --> 06:07:44,285
WHICH IS WHEN WE LOOK AT T-CELL

7480
06:07:44,285 --> 06:07:46,187
ACTIVATION WE CAN USE DIFFERENT

7481
06:07:46,187 --> 06:07:50,525
CYTOKINE AND MARKERS AS READ OUT

7482
06:07:50,525 --> 06:07:52,193
ACTIVATION.

7483
06:07:52,193 --> 06:07:53,995
OLD PAPER LOOKING AT RESPONSE

7484
06:07:53,995 --> 06:07:57,899
AGAINST PEPTIDE AND DIFFERENT

7485
06:07:57,899 --> 06:08:00,101
INTERFERON GAMMA, IL-2 AND 3, TY

7486
06:08:00,101 --> 06:08:05,706
ARE REALLY DIFFERENT RANGES TO E

7487
06:08:05,706 --> 06:08:06,407
TO -- ACTIVATION.

7488
06:08:06,407 --> 06:08:11,712
THIS GOES BACK TO CLASSICAL MODL

7489
06:08:11,712 --> 06:08:13,214
WE DEVELOPED AND THE WAY WE THIK

7490
06:08:13,214 --> 06:08:17,718
OF T-CELL ACTIVATION AND STAGGED

7491
06:08:17,718 --> 06:08:21,522
SET OF INTERACTIONS WHERE EACH

7492
06:08:21,522 --> 06:08:25,626
STEPS OF PCR MIGHT CONNECT TO

7493
06:08:25,626 --> 06:08:26,794
DIFFERENT READ OUTS AND WE MIGHE

7494
06:08:26,794 --> 06:08:31,098
ABLE TO REVEAL DIFFERENT -- CONT

7495
06:08:31,098 --> 06:08:37,705
OF PCR, WE SEE -- YOU'RE

7496
06:08:37,705 --> 06:08:39,507
CONNECTING -- SO MOVING FORWARD

7497
06:08:39,507 --> 06:08:41,909
OVER 20 YEARS, WE CAN'T HAVE

7498
06:08:41,909 --> 06:08:44,111
DATASETS COMING OUT OF THE DATAS

7499
06:08:44,111 --> 06:08:44,912
WITH JUST DATA.

7500
06:08:44,912 --> 06:08:49,617
SO IF YOU DO LIKE THE -- PROCESG

7501
06:08:49,617 --> 06:08:52,119
YOU SEE THERE IS NO RHYME OR REN

7502
06:08:52,119 --> 06:08:52,453
TO THIS DATA.

7503
06:08:52,453 --> 06:08:55,456
VERY HARD TO COMPRESS.

7504
06:08:55,456 --> 06:09:00,294
SO I'M SHOWING YOU SEVEN CYTOKIS

7505
06:09:00,294 --> 06:09:03,731
AND 12 T-CELL TYPES.

7506
06:09:03,731 --> 06:09:11,405
FOUR ACTIVATIONS POINTS --

7507
06:09:11,405 --> 06:09:14,642
DIFFERENT QUANTITY AND TIME POI.

7508
06:09:14,642 --> 06:09:16,210
YOU SEE IF YOU JUST DO SPLASH OF

7509
06:09:16,210 --> 06:09:20,615
DATA, THERE IS NO RHYME OF REAS.

7510
06:09:20,615 --> 06:09:22,817
I'M GOING TO MAKE ANALOGY THAT I

7511
06:09:22,817 --> 06:09:24,118
MADE MANY TIMES AND MAYBE GETTIG

7512
06:09:24,118 --> 06:09:29,323
BORED OF IT BUT IT IS SO NICE -A

7513
06:09:29,323 --> 06:09:31,192
LOT OF NEW TOOLS IN THE FIELD OF

7514
06:09:31,192 --> 06:09:32,426
MACHINE LEARNING WHICH ENABLES U

7515
06:09:32,426 --> 06:09:34,996
TO LOOK AT THIS DATA AND

7516
06:09:34,996 --> 06:09:36,597
AUTOMATICALLY OBTAIN A MODEL AND

7517
06:09:36,597 --> 06:09:38,566
COMPRESS THE DATA AND REALLY

7518
06:09:38,566 --> 06:09:43,838
INTERPRET THE DATA IN A NICE WA.

7519
06:09:43,838 --> 06:09:47,408
SO JUST TO DO THE ANALOGY, THISS

7520
06:09:47,408 --> 06:09:49,610
SOMETHING WE DO IN THE CONTEXT F

7521
06:09:49,610 --> 06:09:49,977
ASTROPHYSICS.

7522
06:09:49,977 --> 06:09:51,646
THIS THE IS WHAT THE SYSTEM LOOD

7523
06:09:51,646 --> 06:09:54,782
LIKE BEFORE.

7524
06:09:54,782 --> 06:09:56,350
PEOPLE MEASURE ANGLES OF PLANETS

7525
06:09:56,350 --> 06:09:59,453
BUT THE MODEL THEY HAD IN TERMSF

7526
06:09:59,453 --> 06:10:01,122
ASTRONOMY WAS THE EARTH WAS THE

7527
06:10:01,122 --> 06:10:01,455
CENTER.

7528
06:10:01,455 --> 06:10:04,258
SO YOU GET VERY BEAUTIFUL ARRAY,

7529
06:10:04,258 --> 06:10:05,259
VERY DIFFICULT GEE NET RE.

7530
06:10:05,259 --> 06:10:07,228
BUT IT'S NOT A VERY USEFUL MODEL

7531
06:10:07,228 --> 06:10:09,830
UNLESS YOU WANT TO SHOOT A ROCKT

7532
06:10:09,830 --> 06:10:10,731
AND GO TO THE MOON.

7533
06:10:10,731 --> 06:10:13,834
IF YOU HAVE THE RIGHT MODEL, ITS

7534
06:10:13,834 --> 06:10:19,106
EASIER TO MODEL AND UNDERSTAND.

7535
06:10:19,106 --> 06:10:20,341
MACHINE LEARNING REDEVELOPED A T

7536
06:10:20,341 --> 06:10:22,743
OF METHODOLOGY.

7537
06:10:22,743 --> 06:10:26,347
SO A PAPER FROM 2018 AND

7538
06:10:26,347 --> 06:10:26,981
INSPIRATION FOR EXAMPLE A LOT OF

7539
06:10:26,981 --> 06:10:32,453
WHAT WE DO FOR FORMULAS THAT WE-

7540
06:10:32,453 --> 06:10:33,754
MACHINE LEARNING TOOLS AND VERY

7541
06:10:33,754 --> 06:10:38,225
COMPLEX DATASETS AND COMPRESSEDD

7542
06:10:38,225 --> 06:10:42,229
WE WANT TO LEARN VERY --

7543
06:10:42,229 --> 06:10:43,531
REPRESENTATION OF THE DATA TO

7544
06:10:43,531 --> 06:10:46,567
RECAPTURE ALL THE COMPLEX SYSTEM

7545
06:10:46,567 --> 06:10:50,037
AND PREDICTABILITY.

7546
06:10:50,037 --> 06:10:53,841
SO YOU SEE THE ANGLE IN COLORS D

7547
06:10:53,841 --> 06:10:58,045
THE BEST WAY TO COMPRESS THE DAA

7548
06:10:58,045 --> 06:11:00,047
AND REPRESENT IS TO PUT THE SUNN

7549
06:11:00,047 --> 06:11:01,449
THE MILT OF THE UNIVERSE AND

7550
06:11:01,449 --> 06:11:04,452
MEASURE ALL THE ANGLES.

7551
06:11:04,452 --> 06:11:06,954
SO I'M NOT SAYING THAT IMMUNOLOY

7552
06:11:06,954 --> 06:11:11,459
IS LIKE ASTROLOGY AND PHYSICS --

7553
06:11:11,459 --> 06:11:12,927
BUT IT'S KIND OF THE IDEA.

7554
06:11:12,927 --> 06:11:15,930
WE WANT TO MOVE TO WHERE TRYINGO

7555
06:11:15,930 --> 06:11:19,033
FIND CLUSTERS, WE ARE GOING TO Y

7556
06:11:19,033 --> 06:11:24,138
TO TAKE THIS COMPLEX AND FUNCTIL

7557
06:11:24,138 --> 06:11:26,741
DATA, MIGHT BE LOOKING AT T-CELL

7558
06:11:26,741 --> 06:11:30,277
DIFFERENTIATION OR AND YOU WANTO

7559
06:11:30,277 --> 06:11:32,046
PUT IN MACHINE LEARNING TOOLS.

7560
06:11:32,046 --> 06:11:35,583
WE ARE TRYING TO LEARN DIFFERENT

7561
06:11:35,583 --> 06:11:40,654
TYPE OF PEPTIDE DERIVED FROM --E

7562
06:11:40,654 --> 06:11:49,797
ARE USING -- VERY LARGE DATASET

7563
06:11:49,797 --> 06:11:52,666
TRYING TO SQUEEZE INTO SMALL SPE

7564
06:11:52,666 --> 06:12:00,641
TO LEARN DIFFERENT CLASSES -- HE

7565
06:12:00,641 --> 06:12:02,543
ON THE LEFT I'M SHOWING YOU WHAT

7566
06:12:02,543 --> 06:12:05,446
THE TWO DIMENSIONAL SPACE IN THE

7567
06:12:05,446 --> 06:12:06,947
MIDDLE LOOKS LIKE.

7568
06:12:06,947 --> 06:12:08,382
SO VERY HIGH DIMENSIONAL SPACE

7569
06:12:08,382 --> 06:12:11,252
WHERE WE HAVE A LOT OF CYTOKINE,

7570
06:12:11,252 --> 06:12:13,087
DEPENDING ON THE TYPE OF TUMOR,D

7571
06:12:13,087 --> 06:12:15,790
THE TYPE OF ONCOGENES, IT'S

7572
06:12:15,790 --> 06:12:18,492
DIFFICULT TO UNDERSTAND THE RHYE

7573
06:12:18,492 --> 06:12:20,261
OR REASON OF THE DIFFERENT

7574
06:12:20,261 --> 06:12:20,561
ACTIVATION.

7575
06:12:20,561 --> 06:12:22,797
VERY SIMPLE DATA MIX WHERE AGAIN

7576
06:12:22,797 --> 06:12:24,698
DEPENDING ON THE QUALITY OF

7577
06:12:24,698 --> 06:12:26,867
ONCOGENES, WE HAVE WILL DIFFERET

7578
06:12:26,867 --> 06:12:29,470
REGIONS OF SPACE DIFFERENTLY

7579
06:12:29,470 --> 06:12:30,070
ORGANIZED.

7580
06:12:30,070 --> 06:12:32,273
I'M GOING TO TRY TO CONVINCE YOO

7581
06:12:32,273 --> 06:12:34,775
USE TOOLS TO LEARN SOMETHING AND

7582
06:12:34,775 --> 06:12:38,078
THEN SHOW YOU SOME REAL NEAT

7583
06:12:38,078 --> 06:12:40,681
APPLICATION WE CAN REUSE TO LEAN

7584
06:12:40,681 --> 06:12:41,715
NEW STUFF.

7585
06:12:41,715 --> 06:12:43,684
SO VALIDATION IS ON THE RIGHT.

7586
06:12:43,684 --> 06:12:51,992
WE CAN QUANTIFY THIS MODEL -- YU

7587
06:12:51,992 --> 06:12:56,197
CAN THINK OF IT AS A MEASURE OF

7588
06:12:56,197 --> 06:12:58,899
BIOPHYSICS AND AGAIN THIS IS DOE

7589
06:12:58,899 --> 06:13:01,669
OBJECTIVELY BY LOOKING WITH MACE

7590
06:13:01,669 --> 06:13:01,936
LEARNING.

7591
06:13:01,936 --> 06:13:03,871
WHEN YOU COMPARE AND MEASURE BY

7592
06:13:03,871 --> 06:13:08,709
CHARACTERIZING THE PEPTIDE ON TE

7593
06:13:08,709 --> 06:13:15,282
PIECE, YOU SEE VERY GOOD

7594
06:13:15,282 --> 06:13:16,650
CORRELATION -- DIFFERENT QUANTIY

7595
06:13:16,650 --> 06:13:19,887
AND THE TUMORS CAUSE DIFFERENT

7596
06:13:19,887 --> 06:13:20,154
ORGANISMS.

7597
06:13:20,154 --> 06:13:21,889
YOU CAN SWITCH TO A HUMAN AND TE

7598
06:13:21,889 --> 06:13:23,290
SAME MODEL APPLIES.

7599
06:13:23,290 --> 06:13:25,192
SO SIMPLY BY CHARACTERIZING THE

7600
06:13:25,192 --> 06:13:28,095
VERY HIGH DIMENSIONAL SPACE AND

7601
06:13:28,095 --> 06:13:29,997
DYNAMICS OF THE CYTOKINE

7602
06:13:29,997 --> 06:13:31,298
PRODUCTION, WE CAN ABLE TO RELEN

7603
06:13:31,298 --> 06:13:33,801
THE MODEL OF THE WAY T-CELLS LOK

7604
06:13:33,801 --> 06:13:36,003
AT THE WORLD THE WAY THEY RECOGE

7605
06:13:36,003 --> 06:13:38,706
DIFFERENT SEQUENCE OF PEPTIDE AD

7606
06:13:38,706 --> 06:13:43,010
RELEARNING IN A WAY -- MODEL OF-

7607
06:13:43,010 --> 06:13:44,912
AGAIN THE BEAUTY OF THE COLOR IE

7608
06:13:44,912 --> 06:13:47,615
CAN GO BACK AND REALLY UNDERSTAD

7609
06:13:47,615 --> 06:13:48,916
WHAT THE CODE IS DOING.

7610
06:13:48,916 --> 06:13:51,819
SO PRACTICALLY WHAT IT DOES, AGN

7611
06:13:51,819 --> 06:13:55,389
TAKE THIS VERY HIGH DIMENSIONAL

7612
06:13:55,389 --> 06:13:59,994
SPACE, PUT IT INTO 2D SPACE, FAY

7613
06:13:59,994 --> 06:14:04,999
SIMPLE AND NOW WE CAN THINK OF O

7614
06:14:04,999 --> 06:14:07,001
PCAs IN A WAY AND VERY

7615
06:14:07,001 --> 06:14:07,301
COMPLICATED.

7616
06:14:07,301 --> 06:14:10,604
THESE TWO VARIABLES TELL US TWO

7617
06:14:10,604 --> 06:14:11,305
DIFFERENT MODES OF T-CELL

7618
06:14:11,305 --> 06:14:11,605
ACTIVATION.

7619
06:14:11,605 --> 06:14:13,908
WHEN WE HAVE A FUNCTION OF -- ON

7620
06:14:13,908 --> 06:14:21,148
THE X AXIS, WE HAVE A WAY THE

7621
06:14:21,148 --> 06:14:25,686
T-CELLS LOOK AT THE WORLD.

7622
06:14:25,686 --> 06:14:28,722
WHEN YOU WRAP UP, YOU SIMPLY WRP

7623
06:14:28,722 --> 06:14:31,692
UP THE POINT OF THE VARIABLE --

7624
06:14:31,692 --> 06:14:36,430
JUST ACTIVATING T-CELLS.

7625
06:14:36,430 --> 06:14:38,999
THE RED VARIABLE NUMBER 2 IS

7626
06:14:38,999 --> 06:14:39,300
INTERESTING.

7627
06:14:39,300 --> 06:14:42,503
WHAT YOU SEE AS YOU RAMP UP, YOU

7628
06:14:42,503 --> 06:14:45,005
FIRST GET COMPONENT AND THEN GOS

7629
06:14:45,005 --> 06:14:46,340
UP AND GETS ACTIVITY AS WELL.

7630
06:14:46,340 --> 06:14:49,510
THIS IS SOMETHING WE KNOW VERY L

7631
06:14:49,510 --> 06:14:53,814
FROM OVER THE YEARS, THE WAY

7632
06:14:53,814 --> 06:14:57,918
T-CELLS LOOK AT THE WORLD -- ONS

7633
06:14:57,918 --> 06:15:00,120
POSITIVE TRYING TO DRIVE ACTIVAN

7634
06:15:00,120 --> 06:15:02,523
AND ONE IS NEGATIVE TRYING TO BK

7635
06:15:02,523 --> 06:15:04,692
THE ACTIVATION AND MAKING SURE T

7636
06:15:04,692 --> 06:15:08,228
YOU DON'T GET -- SO WE CAN USE T

7637
06:15:08,228 --> 06:15:12,099
TO RECLASSIFY ALL THE CELLS WE E

7638
06:15:12,099 --> 06:15:13,534
IN THE LAB IN THE SAMPLES AND WE

7639
06:15:13,534 --> 06:15:17,037
ARE REALLY MEASURING THE

7640
06:15:17,037 --> 06:15:19,640
QUANTITATIVE MANNER AND POSITIVE

7641
06:15:19,640 --> 06:15:23,544
SIGNAL AND NEGATIVE SIGNAL.

7642
06:15:23,544 --> 06:15:27,848
SO, AGAIN VERY ABSTRACT BUT YOUT

7643
06:15:27,848 --> 06:15:32,419
A LOT OF -- ONE YEAR BEFORE COVD

7644
06:15:32,419 --> 06:15:35,522
SHOWED UP AND TOLD US YOU SHOULO

7645
06:15:35,522 --> 06:15:37,658
AND SPEAK -- LEARN ABOUT T-CELL

7646
06:15:37,658 --> 06:15:40,461
ACTIVATION AND SEE IF YOU CAN ME

7647
06:15:40,461 --> 06:15:41,362
SOMETHING MORE RELEVANT.

7648
06:15:41,362 --> 06:15:43,931
THIS IS WHAT WE DID.

7649
06:15:43,931 --> 06:15:46,533
WE SPOKE WITH IN THE POSTDOC INE

7650
06:15:46,533 --> 06:15:50,537
LAB AND THIS MODEL WHERE WE TAKE

7651
06:15:50,537 --> 06:15:53,941
THE ATOMS IN THE PCR AND DO WE

7652
06:15:53,941 --> 06:15:58,579
REALLY NEED THESE VERY COMPLICAD

7653
06:15:58,579 --> 06:15:58,846
MACHINERY?

7654
06:15:58,846 --> 06:15:59,813
NO WOOS DON'T LIKE ALL THE DETA.

7655
06:15:59,813 --> 06:16:02,149
WE WOULD LIKE TO SIMPLIFY THING.

7656
06:16:02,149 --> 06:16:05,052
HERE WE BUILT A MODEL IN THE LA.

7657
06:16:05,052 --> 06:16:09,156
WE HAD THIS DATA CHAIN IMITATED.

7658
06:16:09,156 --> 06:16:11,759
SO, WE LEARN TO WORK WITH HIM AD

7659
06:16:11,759 --> 06:16:13,861
WHAT WE DID IS TAKE THE CELLS AD

7660
06:16:13,861 --> 06:16:16,030
PUT IN ROBOT AND WE CAN AGAIN LK

7661
06:16:16,030 --> 06:16:19,033
AT THE WILDTYPE, WE CAN COMPOSEE

7662
06:16:19,033 --> 06:16:21,835
WAY THEY ARE ACTIVATING IN THE H

7663
06:16:21,835 --> 06:16:24,471
WAY AND WE LOOK AT THE MUTANT

7664
06:16:24,471 --> 06:16:28,809
T-CELLS WHICH DON'T CONTAIN

7665
06:16:28,809 --> 06:16:33,380
PHOSPHORYLATION, SIGNAL BETTER.

7666
06:16:33,380 --> 06:16:37,284
THE FIRST MODE ON THE X AXIS

7667
06:16:37,284 --> 06:16:38,419
DIFFERENT PEPTIDES.

7668
06:16:38,419 --> 06:16:42,156
AND YOU SEE NEW WAVE THOSE

7669
06:16:42,156 --> 06:16:45,159
RESPONSE -- YELLOW MODE WHICH IS

7670
06:16:45,159 --> 06:16:46,760
ACTIVATED AND MORE INTERESTING D

7671
06:16:46,760 --> 06:16:51,165
YOU SEE THE RED MODE WHICH IS

7672
06:16:51,165 --> 06:16:54,368
CORRESPONDING TO THE PATHWAY.

7673
06:16:54,368 --> 06:16:56,770
SO SUDDENLY INSTEAD OF JUST BEIG

7674
06:16:56,770 --> 06:16:59,573
ABSTRACT, YOU SEE THE COMPLETION

7675
06:16:59,573 --> 06:17:02,643
TWO MODES AND MAPS INTO SOME VEY

7676
06:17:02,643 --> 06:17:03,777
EXPLICIT BIOCHEMICAL PATHWAYS.

7677
06:17:03,777 --> 06:17:06,380
SO IN THIS MUTANT, WE ARE MISSIG

7678
06:17:06,380 --> 06:17:11,385
FEEDBACK AND WE SHOULD -- VERY

7679
06:17:11,385 --> 06:17:18,492
DEFECTIVE IN ACTIVATION.

7680
06:17:18,492 --> 06:17:23,097
-- IF YOU WANT SOMETHING

7681
06:17:23,097 --> 06:17:27,668
FUNCTIONAL, WE SCALE DIFFERENT -

7682
06:17:27,668 --> 06:17:29,670
NORMAL REGIME YOU HAVE DIFFERENT

7683
06:17:29,670 --> 06:17:33,774
TYPES OF T-CELLS VERY GOOD.

7684
06:17:33,774 --> 06:17:34,575
WILDTYPE ON THE LEFT.

7685
06:17:34,575 --> 06:17:41,415
AND WHEN YOU MOVE TO -- YOU HAVE

7686
06:17:41,415 --> 06:17:44,284
ONLY TWO CLASSES OF ONCOGENE.

7687
06:17:44,284 --> 06:17:46,787
EITHER NO ACTIVATION OR YOU DO.

7688
06:17:46,787 --> 06:17:51,458
WHEN WE LOOK AT IT THIS WAS

7689
06:17:51,458 --> 06:17:53,093
SOMETHING -- PRETTY CHANCE MODEE

7690
06:17:53,093 --> 06:17:54,995
ARE MISSING NEGATIVE FEEDBACK AD

7691
06:17:54,995 --> 06:17:58,599
ABLE TO INTERPRET A LOT OF

7692
06:17:58,599 --> 06:17:59,299
MEASUREMENTS BEING DONE.

7693
06:17:59,299 --> 06:18:01,401
SO ONE OF THE CONSEQUENCE OF THE

7694
06:18:01,401 --> 06:18:03,670
NEGATIVE FEEDBACK WE EXPECT -- O

7695
06:18:03,670 --> 06:18:07,174
THIS PART IS WHAT MAPS INTO --

7696
06:18:07,174 --> 06:18:10,611
KNOWN AS ANTAGONIST.

7697
06:18:10,611 --> 06:18:13,981
WHEN WE GO WE CAN CHECK IN THE

7698
06:18:13,981 --> 06:18:16,283
AFFECTED MUTANT, NOT ONLY MISSIG

7699
06:18:16,283 --> 06:18:18,485
FEEDBACK BUT NOT ABLE TO ANTAGOE

7700
06:18:18,485 --> 06:18:18,919
RESPONSE.

7701
06:18:18,919 --> 06:18:25,092
SO WE COULD DO AN ASSAY WHERE YU

7702
06:18:25,092 --> 06:18:30,597
MIX -- NORMAL T-CELL YOU GET NIY

7703
06:18:30,597 --> 06:18:33,100
DEFECT -- KEY CREASE CYTOKINE

7704
06:18:33,100 --> 06:18:33,400
PRODUCTION.

7705
06:18:33,400 --> 06:18:35,903
WHEN YOU MOVE TO MUTANT, YOU GET

7706
06:18:35,903 --> 06:18:42,676
INCREASE AND THAT'S WHAT -- JUST

7707
06:18:42,676 --> 06:18:45,012
WANT TO GIVE YOU A SENSE OF WHAE

7708
06:18:45,012 --> 06:18:50,684
ARE DOING IN TERMS OF TRYING TO

7709
06:18:50,684 --> 06:18:53,987
IMMUNOLOGY -- WE CAN GET FROM TE

7710
06:18:53,987 --> 06:18:57,724
ROBOT IN CYTOKINE -- CHARACTERIE

7711
06:18:57,724 --> 06:19:03,797
HIGH DIMENSIONAL SPACE.

7712
06:19:03,797 --> 06:19:06,400
ROBUST MANNER AND PRODUCTIVE ANT

7713
06:19:06,400 --> 06:19:09,203
WORKS WITH CORE SAMPLES AND WORS

7714
06:19:09,203 --> 06:19:12,272
IN COLLABORATION WHERE WE CAN GT

7715
06:19:12,272 --> 06:19:14,408
VERY QUICKLY MOVE AND DO THIS

7716
06:19:14,408 --> 06:19:17,010
MEASUREMENT AND WE CAN REALLY UE

7717
06:19:17,010 --> 06:19:19,313
THAT RICHNESS OF DATASET TO

7718
06:19:19,313 --> 06:19:23,317
COMPRESS DATA IN UNIQUE MANNER,

7719
06:19:23,317 --> 06:19:25,686
TRYING TO LINE IT UP AGAINST

7720
06:19:25,686 --> 06:19:29,323
FUNCTION AND REALLY RE-LEARN T-L

7721
06:19:29,323 --> 06:19:34,995
ACTIVATION AND USE THIS TO REALY

7722
06:19:34,995 --> 06:19:39,700
DESIGN SOME BETTER -- NO CLAPPI.

7723
06:19:39,700 --> 06:19:50,077
WE HAVE A SECOND PART.

7724
06:20:01,588 --> 06:20:03,090
>> THE TITLE OF MY TALK
HAS

7725
06:20:03,090 --> 06:20:03,490
CHANGED.

7726
06:20:03,490 --> 06:20:05,292
PART OF IT IS WE HAD CHANGES INE

7727
06:20:05,292 --> 06:20:06,894
PROGRAM AND THEN BECAUSE OF LOTF

7728
06:20:06,894 --> 06:20:08,528
DIFFERENT ISSUES, I DECIDED I WD

7729
06:20:08,528 --> 06:20:10,931
BE THE LAST SPEAKER.

7730
06:20:10,931 --> 06:20:12,499
IT MADE SENSE TO SORT OF GIVE YU

7731
06:20:12,499 --> 06:20:13,433
THE SECOND PART OF THIS.

7732
06:20:13,433 --> 06:20:16,703
AND I WILL TRY TO CONVINCE YOU

7733
06:20:16,703 --> 06:20:18,805
ALSO -- SOME OF YOU MAY BE HARDR

7734
06:20:18,805 --> 06:20:20,307
TO CONVINCE THAN OTHERS BUT I WL

7735
06:20:20,307 --> 06:20:21,408
TRY TO CONVINCE YOU THAT EVEN

7736
06:20:21,408 --> 06:20:25,078
SOMETHING LIKE THINKING ABOUT

7737
06:20:25,078 --> 06:20:27,014
CHIMERIC ANTIGEN RECEPTORS DOES

7738
06:20:27,014 --> 06:20:29,316
HAVE A PLACE IN A SYMPOSIUM ON

7739
06:20:29,316 --> 06:20:30,317
BASIC IMMUNOLOGY.

7740
06:20:30,317 --> 06:20:32,319
WITH THAT AS MY CHALLENGE I WILL

7741
06:20:32,319 --> 06:20:34,922
MOVE FORWARD WITH THAT.

7742
06:20:34,922 --> 06:20:37,758
SO, WE ARE GOING TO COME BACK TO

7743
06:20:37,758 --> 06:20:40,627
TWO CHIMERIC ANTIGEN RECEPTORS D

7744
06:20:40,627 --> 06:20:43,597
THE VAST MAJORITY ARE AWARE THEY

7745
06:20:43,597 --> 06:20:46,833
ARE MADE UP OF BINDING SEGMENT O

7746
06:20:46,833 --> 06:20:48,335
TUMOR ANTIGEN AND THEN YOU HAVE

7747
06:20:48,335 --> 06:20:50,203
SIGNALING THAT GOES ON AND THAT

7748
06:20:50,203 --> 06:20:51,805
SIGNALING IS GOING TO LEAD TO TE

7749
06:20:51,805 --> 06:20:56,643
DEATH OF YOUR CELL IT'S REALLY

7750
06:20:56,643 --> 06:20:59,746
IMPORTANT TO SAY HERE IN THIS

7751
06:20:59,746 --> 06:21:00,614
MEETING, FRONTIERS AND BASIC

7752
06:21:00,614 --> 06:21:01,949
IMMUNOLOGY, ALL OF THIS CAN BE E

7753
06:21:01,949 --> 06:21:03,183
ONLY BECAUSE OF YEARS AND YEARSF

7754
06:21:03,183 --> 06:21:04,918
WORK ON TRYING TO UNDERSTAND HOW

7755
06:21:04,918 --> 06:21:12,159
THE T-CELL RECEPTOR WORKS.

7756
06:21:12,159 --> 06:21:13,927
WHEN I THINK ABOUT THE FOUR

7757
06:21:13,927 --> 06:21:15,228
PEOPLE -- I'M USING THE MICROPHE

7758
06:21:15,228 --> 06:21:16,029
HERE TOO.

7759
06:21:16,029 --> 06:21:18,231
THE FOUR PEOPLE WHO I THINK OF S

7760
06:21:18,231 --> 06:21:20,734
HAVING GIVEN AT LEAST ME AND THE

7761
06:21:20,734 --> 06:21:25,539
COMMUNITY A HUGE AMOUNT OF

7762
06:21:25,539 --> 06:21:27,941
INFORMATION ON TCR SIGNALING.

7763
06:21:27,941 --> 06:21:30,143
THERE IS ONE PERSON WHO ISN'T H,

7764
06:21:30,143 --> 06:21:30,944
ART WISE.

7765
06:21:30,944 --> 06:21:33,347
SO JUST PUTTING THAT TOGETHER, E

7766
06:21:33,347 --> 06:21:36,450
QUESTION BECOMES BASED ON WHAT -

7767
06:21:36,450 --> 06:21:41,955
IS MY -- DOES THE THING WORK?

7768
06:21:41,955 --> 06:21:52,165
THE POINTER?

7769
06:21:52,499 --> 06:21:57,137
SO ONE OF THE THINGS THAT HAPPES

7770
06:21:57,137 --> 06:21:58,672
THERE -- SORRY.

7771
06:21:58,672 --> 06:22:00,140
ONE OF THE THINGS THAT HAPPENS N

7772
06:22:00,140 --> 06:22:04,044
TERMS OF THINKING ABOUT WHAT WAS

7773
06:22:04,044 --> 06:22:06,346
JUST SAID, IS THERE -- WHAT IS E

7774
06:22:06,346 --> 06:22:07,114
INTERACTION BETWEEN THE SIGNALIG

7775
06:22:07,114 --> 06:22:08,548
THAT IS HAPPENING FROM THE CAR,

7776
06:22:08,548 --> 06:22:10,751
WHICH IS WHAT YOU'RE DOING WHEN

7777
06:22:10,751 --> 06:22:11,952
YOU'RE PUTTING INTO THE CELL AND

7778
06:22:11,952 --> 06:22:14,254
THE SIGNALING HAPPENING FROM THE

7779
06:22:14,254 --> 06:22:15,055
T-CELL RECEPTOR.

7780
06:22:15,055 --> 06:22:16,757
A LOT OF WORK WHERE PEOPLE HAVE

7781
06:22:16,757 --> 06:22:18,859
TAKEN THE T-CELL RECEPTOR OUT.

7782
06:22:18,859 --> 06:22:20,761
AND ALSO A FAIR AMOUNT OF DATA W

7783
06:22:20,761 --> 06:22:23,363
THAT SAYS THAT THE ENDOGENOUS

7784
06:22:23,363 --> 06:22:25,065
T-CELL RECEPTOR HAS IMPORTANCE R

7785
06:22:25,065 --> 06:22:26,933
THE CAR AND THE CAR IS THE

7786
06:22:26,933 --> 06:22:28,769
ASSOCIATE THE WITH SPECIFIC

7787
06:22:28,769 --> 06:22:29,970
ENDOGENOUS TCRs.

7788
06:22:29,970 --> 06:22:32,873
SO COMING BACK TO WHAT YOU HEARD

7789
06:22:32,873 --> 06:22:34,574
ABOUT FROM GREG, WE CAN TAKE THE

7790
06:22:34,574 --> 06:22:35,976
MODELS THAT THEY HAVE DEVELOPEDN

7791
06:22:35,976 --> 06:22:37,477
THEIR LAB AND WE CAN NOW LOOK AT

7792
06:22:37,477 --> 06:22:39,379
THIS AND THIS IS A MOUSE MODEL.

7793
06:22:39,379 --> 06:22:41,148
AND WE ARE LOOKING AT WHAT WE HD

7794
06:22:41,148 --> 06:22:42,849
ABOUT BEFORE IN TERMS OF THE LAT

7795
06:22:42,849 --> 06:22:45,452
SPACE AND SEEING WHAT HAPPENS WN

7796
06:22:45,452 --> 06:22:47,954
WE TAKE DIFFERENT ANTIGENS AGAIT

7797
06:22:47,954 --> 06:22:50,357
THE HUMAN TCR.

7798
06:22:50,357 --> 06:22:53,627
SO OT1 AND ALMOST NO RESPONSIVES

7799
06:22:53,627 --> 06:22:55,395
AND THEN GETTING TO HIGHER AND

7800
06:22:55,395 --> 06:22:56,963
HIGHER LEVELS OF ANTIGEN AND YOU

7801
06:22:56,963 --> 06:22:58,765
SEE MORE AND MORE RESPONSES.

7802
06:22:58,765 --> 06:22:59,966
WHAT HAPPENS WHEN YOU PUT IN A ?

7803
06:22:59,966 --> 06:23:02,569
SO YOU CAN SEE HERE THE LEVEL OF

7804
06:23:02,569 --> 06:23:04,971
RESPONSIVENESS THAT WE HAD WITH

7805
06:23:04,971 --> 06:23:06,573
CD19 CAR IS ACTUALLY MUCH LOWER

7806
06:23:06,573 --> 06:23:08,675
THAN WHAT WE HAD WHEN WE HAVE OR

7807
06:23:08,675 --> 06:23:10,777
BEST T-CELL RECEPTOR WITH A STRG

7808
06:23:10,777 --> 06:23:11,211
ANTIGEN.

7809
06:23:11,211 --> 06:23:14,314
SO A CD19 CAR WHICH IS REALLY TE

7810
06:23:14,314 --> 06:23:15,382
SORT OF ROLLS-ROYCE WHEN WE THIK

7811
06:23:15,382 --> 06:23:17,784
ABOUT IN TERMS OF CAR IS NOT

7812
06:23:17,784 --> 06:23:20,487
SIGNALING AS WELL AS OUR TCR

7813
06:23:20,487 --> 06:23:20,821
ANTIGENS.

7814
06:23:20,821 --> 06:23:22,389
BUT EACH MORE INTERESTING WHAT

7815
06:23:22,389 --> 06:23:32,966
HAPPENS IS, WE DON'T -- THE LOWT

7816
06:23:34,067 --> 06:23:37,537
LEVEL OF ANTIGEN HERE IS A LEVEF

7817
06:23:37,537 --> 06:23:38,271
RESPONSIVENESS LOWER THAN WHAT

7818
06:23:38,271 --> 06:23:40,774
YOU'RE SEEING WITH CD19 CAR.

7819
06:23:40,774 --> 06:23:42,776
SO THE QUESTION THEN BECOMES HOW

7820
06:23:42,776 --> 06:23:43,777
DOES THIS ALL WORK?

7821
06:23:43,777 --> 06:23:46,046
IS THERE AN INTERACTION AND WHAS

7822
06:23:46,046 --> 06:23:47,981
THE INTERACTION WHEN WE'RE LOOKG

7823
06:23:47,981 --> 06:23:52,219
AT A CD19 CAR AND AN OT1TCR?

7824
06:23:52,219 --> 06:23:55,021
WE DID THAT TO MODEL THESE THINS

7825
06:23:55,021 --> 06:23:55,222
FIRST.

7826
06:23:55,222 --> 06:23:56,990
WON'T TELL YOU A HUGE AMOUNT OF

7827
06:23:56,990 --> 06:23:57,190
DATA.

7828
06:23:57,190 --> 06:23:58,925
ALL THIS DATA IS UNPUBLISHED.

7829
06:23:58,925 --> 06:23:59,993
WE DECIDED TO PRESENT IT HERE

7830
06:23:59,993 --> 06:24:01,194
BECAUSE WE ARE IN THE PROCESS OF

7831
06:24:01,194 --> 06:24:02,696
TRYING TO THINK WHERE TO SEND IT

7832
06:24:02,696 --> 06:24:02,996
OUT.

7833
06:24:02,996 --> 06:24:05,699
SO WE WOULD BE HAPPY TO HAVE YOR

7834
06:24:05,699 --> 06:24:05,966
COMMENTS.

7835
06:24:05,966 --> 06:24:07,601
IT ALSO MEANS WE TAKE A SLIGHT K

7836
06:24:07,601 --> 06:24:10,103
BY SHARING TO A LARGE ROOM OF

7837
06:24:10,103 --> 06:24:10,337
PEOPLE.

7838
06:24:10,337 --> 06:24:11,905
BUT SINCE YOU'RE ALL OUR BEST

7839
06:24:11,905 --> 06:24:18,678
FRIENDS, WE KNOW THAT'S NOT AN

7840
06:24:18,678 --> 06:24:18,879
ISSUE.

7841
06:24:18,879 --> 06:24:21,915
WHAT WOULD EXPECT IS IF YOU HAVA

7842
06:24:21,915 --> 06:24:32,526
TCR SIGNAL WITH NOTHING AT ALL S

7843
06:24:40,867 --> 06:24:48,208
IS WRONG AND I APOLOGIZE.

7844
06:24:48,208 --> 06:24:50,443
THIS IS THE WRONG THING.

7845
06:24:50,443 --> 06:24:52,212
THIS IS WHAT WE ANTICIPATE THE E

7846
06:24:52,212 --> 06:24:52,913
RESULT WOULD BE.

7847
06:24:52,913 --> 06:24:54,314
IF YOU HAVE A CAR BY ITSELF, IT

7848
06:24:54,314 --> 06:24:57,117
WOULD GIVE YOU SOME RESPONSE.

7849
06:24:57,117 --> 06:24:58,818
THE MICE WOULD INDIVIDUALLY DIE.

7850
06:24:58,818 --> 06:25:00,921
THAT IF YOU HAD A CAR WITH A STG

7851
06:25:00,921 --> 06:25:02,255
TCR THAT WOULD GIVE YOU A REALLY

7852
06:25:02,255 --> 06:25:03,290
GOOD RESPONSE.

7853
06:25:03,290 --> 06:25:04,925
AND THEN IF YOU HAD A CAR WITH A

7854
06:25:04,925 --> 06:25:06,927
WEAK TCR IT WOULD BE SOMEWHERE N

7855
06:25:06,927 --> 06:25:07,627
THE MIDDLE.

7856
06:25:07,627 --> 06:25:15,001
BUT THAT'S NOT THE CASE.

7857
06:25:15,001 --> 06:25:16,536
THIS IS THE WRONG VERSION.

7858
06:25:16,536 --> 06:25:17,904
T-CELLS ARE BAD AT MATH AND THE

7859
06:25:17,904 --> 06:25:19,072
EXPERIMENTAL RESULT IS BASICALLY

7860
06:25:19,072 --> 06:25:21,408
THAT IN FACT THIS IS THE REAL

7861
06:25:21,408 --> 06:25:23,843
RESULTS WHICH IS IF YOU HAVE A K

7862
06:25:23,843 --> 06:25:25,679
TCR, THOSE MICE DIE MUCH EARLIE.

7863
06:25:25,679 --> 06:25:28,014
NOT ONLY DO THEY DIE MUCH EARLI,

7864
06:25:28,014 --> 06:25:31,218
BUT WHEN YOU LOOK AT CYTOKINES Y

7865
06:25:31,218 --> 06:25:33,820
ARE ALSO IN A CONTEXT WHERE THEY

7866
06:25:33,820 --> 06:25:35,789
ARE MUCH LOWER THAN WHAT YOU HAE

7867
06:25:35,789 --> 06:25:37,023
WITH A CAR ALONE.

7868
06:25:37,023 --> 06:25:39,292
YOU'RE HAVING AN EFFECT THAT IS

7869
06:25:39,292 --> 06:25:39,626
ANTAGONISTIC.

7870
06:25:39,626 --> 06:25:41,828
I THOUGHT ABOUT THIS, I LISTENEO

7871
06:25:41,828 --> 06:25:44,931
THE TALKS THIS MORNING FROM BOTH

7872
06:25:44,931 --> 06:25:46,132
LARRY AND JULIAN THINKING ABOUT

7873
06:25:46,132 --> 06:25:49,135
WHAT WE THINK ABOUT IN TERMS OFC

7874
06:25:49,135 --> 06:25:50,136
GAMMA ACTIVATION AND YOU CAN SEE

7875
06:25:50,136 --> 06:25:53,039
THAT IF WE HAVE A CD19 LOW CAR,D

7876
06:25:53,039 --> 06:25:55,842
WE LOOK AT T ARE CR ANTIGEN

7877
06:25:55,842 --> 06:25:57,510
STRENGTHS WITH JUST THE CAR ALO,

7878
06:25:57,510 --> 06:25:59,646
YOU HAVE A CERTAIN RESPONSE.

7879
06:25:59,646 --> 06:26:01,414
IF YOU THEN LOOK AND SEE WHAT

7880
06:26:01,414 --> 06:26:04,351
HAPPENS WHEN YOU HAVE LOW LEVELF

7881
06:26:04,351 --> 06:26:06,419
TCR ANTIGENS IT'S GONE DOWN AND

7882
06:26:06,419 --> 06:26:08,154
IT'S WHEN YOU HAVE VERY HIGH LES

7883
06:26:08,154 --> 06:26:10,724
OF ANTIGEN THAT IT COMES BACK U.

7884
06:26:10,724 --> 06:26:12,459
LOOKING AT MULTIPLE EXPERIMENTSU

7885
06:26:12,459 --> 06:26:14,728
CAN SEE THAT YOU CAN MODEL THISD

7886
06:26:14,728 --> 06:26:17,631
THIS IS WHAT YOU SEE WHEN YOU ML

7887
06:26:17,631 --> 06:26:18,331
IT.

7888
06:26:18,331 --> 06:26:20,233
SO, WE CAN MODEL THIS AND THIS S

7889
06:26:20,233 --> 06:26:22,135
THE KIND OF THING THAT YOU HEARD

7890
06:26:22,135 --> 06:26:24,037
ABOUT BEFORE.

7891
06:26:24,037 --> 06:26:25,538
WE CAN THEN MODEL FIT IT.

7892
06:26:25,538 --> 06:26:29,943
WE CAN MODEL FIT IT WITH ICANS

7893
06:26:29,943 --> 06:26:32,712
WHERE WE HAVE THREE ICHAN AND TN

7894
06:26:32,712 --> 06:26:34,814
WE CAN USE A MATHEMATICAL MODELD

7895
06:26:34,814 --> 06:26:38,918
WILL WHEN WE USE THIS MATHEMATIL

7896
06:26:38,918 --> 06:26:40,620
EQUATION YOU CAN SEE WHEN YOU HE

7897
06:26:40,620 --> 06:26:42,956
A WEAK TCR ANTIGEN, MOST OF THE

7898
06:26:42,956 --> 06:26:44,457
FEEDBACK YOU'RE GETTING IS

7899
06:26:44,457 --> 06:26:44,724
NEGATIVE.

7900
06:26:44,724 --> 06:26:47,227
SO YOU'RE CREATING AN ANTAGONISC

7901
06:26:47,227 --> 06:26:48,228
FEEDBACK.

7902
06:26:48,228 --> 06:26:50,263
SO THE QUESTION BECAME, CAN WE E

7903
06:26:50,263 --> 06:26:52,332
THIS IN THE CONTEXT WHICH WOULDE

7904
06:26:52,332 --> 06:26:52,632
THERAPEUTIC?

7905
06:26:52,632 --> 06:26:54,734
BECAUSE ONE OF THE ISSUES WITH S

7906
06:26:54,734 --> 06:26:57,937
IS THAT THE CAR IS NOT ABLE TO E

7907
06:26:57,937 --> 06:26:59,939
THE DIFFERENCE BETWEEN AN ANTIGN

7908
06:26:59,939 --> 06:27:02,042
THAT IS IT ON A HEALTHY CELL ANN

7909
06:27:02,042 --> 06:27:04,244
ANTIGEN THAT IS ON A TUMOR CELL.

7910
06:27:04,244 --> 06:27:06,613
IT'S GOING TO KILL BOTH OF THOS.

7911
06:27:06,613 --> 06:27:08,248
WHAT IS USUALLY DIFFERENT AND WH

7912
06:27:08,248 --> 06:27:11,151
WE ARE NOT TARGETING WITH A CARN

7913
06:27:11,151 --> 06:27:12,752
GENERAL, THE FACT THAT YOU'RE GG

7914
06:27:12,752 --> 06:27:14,754
TO HAVE PROTEINS MUTATED BECAUSE

7915
06:27:14,754 --> 06:27:15,955
YOU HAVE MANNER MORE PEWITATIONN

7916
06:27:15,955 --> 06:27:18,458
A TUMOR CELL THAN YOU HAVE A

7917
06:27:18,458 --> 06:27:19,426
HEALTHY CELL.

7918
06:27:19,426 --> 06:27:21,828
SO IN THE CONTEXT OF CD19 CARS,

7919
06:27:21,828 --> 06:27:23,129
WHEN YOU LOOK AT THIS EFFECT, WH

7920
06:27:23,129 --> 06:27:27,434
IS WHAT WE CALL AN EFFECT OF ON

7921
06:27:27,434 --> 06:27:29,903
TARGET BUT OFF TUMOR TOXICITY,

7922
06:27:29,903 --> 06:27:31,838
THAT'S NOT CAUSING HUGE AMOUNTSF

7923
06:27:31,838 --> 06:27:33,239
PROBLEMS BECAUSE YOU'RE KILLINGF

7924
06:27:33,239 --> 06:27:36,042
YOUR CD19 POSITIVE LEUKEMIA ANDE

7925
06:27:36,042 --> 06:27:38,945
FACT THAT YOU'RE KILLING OFF THE

7926
06:27:38,945 --> 06:27:40,347
POSITIVE B CELLS IS SOMETHING TT

7927
06:27:40,347 --> 06:27:41,047
YOU CAN DEAL WITH.

7928
06:27:41,047 --> 06:27:43,450
YOU CAN GIVE IMMUNOGLOBULIN.

7929
06:27:43,450 --> 06:27:44,918
BUT IT'S NOT SOMETHING THAT IS

7930
06:27:44,918 --> 06:27:46,786
GOING TO KILL YOUR PATIENT.

7931
06:27:46,786 --> 06:27:50,457
AT LEAST IN GENERAL.

7932
06:27:50,457 --> 06:27:52,559
AND THEN WE KNOW THE LONGER YOU

7933
06:27:52,559 --> 06:27:54,761
HAVE B-CELL APLASIA THAT'S A GOD

7934
06:27:54,761 --> 06:27:56,529
SIGN IN TERMS OF HAVING A CAR TT

7935
06:27:56,529 --> 06:27:58,531
WILL BE FUNCTIONAL.

7936
06:27:58,531 --> 06:28:01,668
IN THE CONTEXT OF SOLID TUMORS,E

7937
06:28:01,668 --> 06:28:03,570
OF THE PROBLEMS IS THAT A LOT OF

7938
06:28:03,570 --> 06:28:07,474
THE TARGETS WE HAVE IN SOLID TUS

7939
06:28:07,474 --> 06:28:09,876
HAVE TARGETS IN TISSUES THAT ARE

7940
06:28:09,876 --> 06:28:10,176
CRUCIAL.

7941
06:28:10,176 --> 06:28:11,778
SO FOR EXAMPLE, WHILE WE WANT TO

7942
06:28:11,778 --> 06:28:14,414
KILL OFF A HER2 POSITIVE CARCINA

7943
06:28:14,414 --> 06:28:16,049
YOU DON'T WANT TO KILL OFF LUNG

7944
06:28:16,049 --> 06:28:18,485
CELLS THAT ARE HER2 POSITIVE

7945
06:28:18,485 --> 06:28:19,552
BECAUSE THAT WOULD CAUSE

7946
06:28:19,552 --> 06:28:20,687
RESPIRATORY FAILURE AND DEATH.

7947
06:28:20,687 --> 06:28:22,889
THE QUESTION OF THIS YIN AND YAG

7948
06:28:22,889 --> 06:28:25,058
AND HOW TO DEAL WITH IT AND THE

7949
06:28:25,058 --> 06:28:27,360
TOXICITIES IS A HUGE PROBLEM.

7950
06:28:27,360 --> 06:28:30,063
AND IT'S DEFINITELY A LARGE PARF

7951
06:28:30,063 --> 06:28:33,700
THE REASON WHY IT'S BEEN SO MUCH

7952
06:28:33,700 --> 06:28:35,168
SIMPLER -- ONLY PART OF THE ISSE

7953
06:28:35,168 --> 06:28:38,872
BUT WHY IT'S BEEN SIMPLER TO HAE

7954
06:28:38,872 --> 06:28:40,373
SUCCESS IN THE TREATMENT OF LIQD

7955
06:28:40,373 --> 06:28:45,278
TUMORS AS COMPARED TO SOLID.

7956
06:28:45,278 --> 06:28:46,880
SO WHAT IS THE COMMUNITY?

7957
06:28:46,880 --> 06:28:49,549
THE COMMUNITY HAS DONE ALL SORTF

7958
06:28:49,549 --> 06:28:50,683
DIFFERENT THINGS AND DESIGNS TRG

7959
06:28:50,683 --> 06:28:52,619
TO SAY THAT YOU NEED TO -- IN OR

7960
06:28:52,619 --> 06:28:54,187
TO HAVE A CAR TO WORK FOR EXAMPE

7961
06:28:54,187 --> 06:28:56,890
AGAINST A SOLID TUMOR, YOU WOULD

7962
06:28:56,890 --> 06:28:58,591
HAVE TWO DIFFERENT TARGETS AND Y

7963
06:28:58,591 --> 06:29:00,093
BOTH HAVE TO BE THERE IN ORDER O

7964
06:29:00,093 --> 06:29:01,594
GET A RESPONSE.

7965
06:29:01,594 --> 06:29:03,696
OR THAT ONE HAS TO BE THERE ANDE

7966
06:29:03,696 --> 06:29:04,998
OTHER HAS TO BE GONE.

7967
06:29:04,998 --> 06:29:06,499
AND THAT YOU CAN PUT IT IN AND U

7968
06:29:06,499 --> 06:29:08,401
HAVE TO HAVE TWO TARGETS IN ORDR

7969
06:29:08,401 --> 06:29:10,170
TO GET SIGNALING AND THAT'S CALD

7970
06:29:10,170 --> 06:29:10,904
A LINKER.

7971
06:29:10,904 --> 06:29:13,072
SO THERE HAS BEEN A HUGE AMOUNTF

7972
06:29:13,072 --> 06:29:13,606
WORK ON THIS.

7973
06:29:13,606 --> 06:29:15,809
A LOT OF THESE PAPERS COME OUT N

7974
06:29:15,809 --> 06:29:17,477
SCIENCE, CELL, NATURE, BECAUSE

7975
06:29:17,477 --> 06:29:20,513
THERE IS A HUGE REQUEST TO SEE W

7976
06:29:20,513 --> 06:29:21,681
THIS WORKS.

7977
06:29:21,681 --> 06:29:23,516
BUT THERE ARE SOME SIGNIFICANT

7978
06:29:23,516 --> 06:29:24,784
LIMITATIONS EVEN WITH WHAT HAS N

7979
06:29:24,784 --> 06:29:28,321
DONE WITH WHAT WE CALL THE LOGIC

7980
06:29:28,321 --> 06:29:28,521
GATES.

7981
06:29:28,521 --> 06:29:30,290
AND THE PROBLEM IS WITH A CAR,

7982
06:29:30,290 --> 06:29:32,525
YOU'RE LOOKING AT SURFACE ANTIG.

7983
06:29:32,525 --> 06:29:34,761
BUT A HUGE AMOUNT OF THE PROTEIS

7984
06:29:34,761 --> 06:29:39,499
IN THE CELL IS NON SURFACED, ITS

7985
06:29:39,499 --> 06:29:39,833
INTRACELLULAR.

7986
06:29:39,833 --> 06:29:41,601
OVER 85% OF THE PROTEINS IN OUR

7987
06:29:41,601 --> 06:29:42,602
CELL ARE INSIDE THE CELL.

7988
06:29:42,602 --> 06:29:43,703
AND YOU WOULDN'T BE GETTING THAT

7989
06:29:43,703 --> 06:29:45,104
WITH A CAR.

7990
06:29:45,104 --> 06:29:47,907
SO YOU'RE ELIMINATING 85% OF THE

7991
06:29:47,907 --> 06:29:49,108
POSSIBLE TARGETS THAT YOU COULD

7992
06:29:49,108 --> 06:29:49,909
EVEN HAVE.

7993
06:29:49,909 --> 06:29:51,811
AND THEN THERE ARE OTHER ISSUES

7994
06:29:51,811 --> 06:29:54,714
THAT WE HAVE IN TERMS OF TISSUES

7995
06:29:54,714 --> 06:29:56,416
RESTRICTIONS, ANTIGENS, LOGISTIL

7996
06:29:56,416 --> 06:29:56,716
CHALLENGES.

7997
06:29:56,716 --> 06:29:59,519
SO THE QUESTION WE ASKED IS, CAE

7998
06:29:59,519 --> 06:30:00,920
CREATE A SITUATION WHERE IN THE

7999
06:30:00,920 --> 06:30:03,122
CONTEXT OF A STRONG ANTIGEN THAS

8000
06:30:03,122 --> 06:30:06,526
BEING SEEN BY THE TCR, WE WOULD

8001
06:30:06,526 --> 06:30:08,127
ENHANCE THE ACTIVATION.

8002
06:30:08,127 --> 06:30:10,330
WHEREAS WITH A WEAK ANTIGEN THEE

8003
06:30:10,330 --> 06:30:12,432
COULD USE THIS AS A WAY OF

8004
06:30:12,432 --> 06:30:13,833
RESTRAINING AND NOT HAVING ON

8005
06:30:13,833 --> 06:30:17,437
TARGET OFF TUMOR TOXICITY.

8006
06:30:17,437 --> 06:30:19,038
SO THE QUESTION IS, WILL THAT

8007
06:30:19,038 --> 06:30:19,272
HAPPEN?

8008
06:30:19,272 --> 06:30:24,844
IN ORDER TO DO THIS, WE, AND ITS

8009
06:30:24,844 --> 06:30:26,713
REALLY -- SITTING NEXT TO THE DR

8010
06:30:26,713 --> 06:30:28,414
AND RESPONSIBLE FOR A HUGE AMOUT

8011
06:30:28,414 --> 06:30:32,919
OF THIS WORK TOGETHER WITH FRANS

8012
06:30:32,919 --> 06:30:35,321
AND GEORGE TO DESIGN AND PUT INO

8013
06:30:35,321 --> 06:30:40,426
THAT CONSTRUCT A TCR AGAINST HH,

8014
06:30:40,426 --> 06:30:43,029
WHICH IS MUTATED IN SEVERAL TYPS

8015
06:30:43,029 --> 06:30:44,731
OF DIFFERENT KINDS OF TUMORS.

8016
06:30:44,731 --> 06:30:47,133
AND TO DO THAT WITH A REPORTER.

8017
06:30:47,133 --> 06:30:48,835
AND THEN THE QUESTION BECOMES, N

8018
06:30:48,835 --> 06:30:51,804
WE USE THIS NOW TO CHANGE WHAT S

8019
06:30:51,804 --> 06:30:54,140
OCCURRING IN THE CONTEXT OF TISE

8020
06:30:54,140 --> 06:30:57,343
CELLS AND TUMOR CELLS?

8021
06:30:57,343 --> 06:30:59,045
SO THE FIRST QUESTION IS, WE STT

8022
06:30:59,045 --> 06:31:01,714
TO LOOK AT THE RESPONSIVENESS OF

8023
06:31:01,714 --> 06:31:03,416
THIS TO TISSUE CELL ANTIGEN ANDE

8024
06:31:03,416 --> 06:31:04,851
ARE ALWAYS COMPARING WITH WHAT E

8025
06:31:04,851 --> 06:31:09,022
ARE SEEING FOR HER2 CAR.

8026
06:31:09,022 --> 06:31:13,159
SO WITH SELF ANTIGEN, OUR HHAT R

8027
06:31:13,159 --> 06:31:16,462
TWO CAR AGAINST TISSUE IS HAVING

8028
06:31:16,462 --> 06:31:21,968
LOWER LEVELS OF INTERFERON GAMMA

8029
06:31:21,968 --> 06:31:23,236
AND OTHERS AND AGAINST THE TUMOR

8030
06:31:23,236 --> 06:31:25,505
WHERE WE HAVE THE NEO-ANTIGEN OF

8031
06:31:25,505 --> 06:31:28,441
THE HHAT WE HAVE INCREASES IN SE

8032
06:31:28,441 --> 06:31:31,344
OF THESE INCLUDING INTERFERON GA

8033
06:31:31,344 --> 06:31:32,345
AND IL-2.

8034
06:31:32,345 --> 06:31:35,148
SO IT IS EXCITING TO SEE THAT WE

8035
06:31:35,148 --> 06:31:36,549
HAVE THIS YIN YANG WE CAN PLAY H

8036
06:31:36,549 --> 06:31:39,252
IN TERMS OF THE SELF ANTIGEN,

8037
06:31:39,252 --> 06:31:41,054
NEO-ANTIGEN CONTEXT.

8038
06:31:41,054 --> 06:31:41,955
SO WHAT HAPPENS WHEN WE START TO

8039
06:31:41,955 --> 06:31:42,956
LOOK AT IT?

8040
06:31:42,956 --> 06:31:44,257
SO HERE WE ARE LOOKING AT WHAT

8041
06:31:44,257 --> 06:31:46,960
HAPPENS IF WE HAVE THE TCR ALON,

8042
06:31:46,960 --> 06:31:49,562
THE HER2 CAR ALONE OR THE HER2 R

8043
06:31:49,562 --> 06:31:53,633
WITH AUTO TCR AGAINST HHAT.

8044
06:31:53,633 --> 06:31:57,036
SO IF YOU'RE NOT EXPRESSING HHA,

8045
06:31:57,036 --> 06:32:00,840
YOU WOULD EXPECT YOUR HER2 CAR D

8046
06:32:00,840 --> 06:32:03,776
HHAT WOULD BE THE SAME AND THEY

8047
06:32:03,776 --> 06:32:04,978
WOULD BLOCK PROLIFERATION IN THE

8048
06:32:04,978 --> 06:32:05,478
SAME WAY.

8049
06:32:05,478 --> 06:32:06,846
AND THAT'S THE CASE.

8050
06:32:06,846 --> 06:32:11,451
AND ALSO THE HHAT, TCR IS NOT DG

8051
06:32:11,451 --> 06:32:11,718
ANYTHING.

8052
06:32:11,718 --> 06:32:14,153
WHAT HAPPENS IF YOU HAVE THE TUR

8053
06:32:14,153 --> 06:32:14,387
TISSUE?

8054
06:32:14,387 --> 06:32:16,656
NOW IN THE TUMOR TISSUE WE HAVEE

8055
06:32:16,656 --> 06:32:16,956
NEO-ANTIGEN.

8056
06:32:16,956 --> 06:32:19,459
SO WITH THAT, YOU CAN SEE THAT E

8057
06:32:19,459 --> 06:32:21,160
TCR ITSELF IS BLOCKING

8058
06:32:21,160 --> 06:32:22,962
PROLIFERATION COMPARED TO THE

8059
06:32:22,962 --> 06:32:23,196
CONTROL.

8060
06:32:23,196 --> 06:32:26,766
AND IN THIS CASE, BOTH AGAIN THE

8061
06:32:26,766 --> 06:32:29,435
HER2 CAR AND THE MIXED CAR IS WH

8062
06:32:29,435 --> 06:32:32,171
THE TCR KILLING AT THE SAME RAT.

8063
06:32:32,171 --> 06:32:33,673
SO WHAT HAPPENS WHEN WE HAVE

8064
06:32:33,673 --> 06:32:33,906
TISSUE?

8065
06:32:33,906 --> 06:32:35,475
BECAUSE THIS IS THE REAL QUESTI.

8066
06:32:35,475 --> 06:32:38,077
NOW WE DON'T HAVE A NEW ANTIGENE

8067
06:32:38,077 --> 06:32:39,646
HAVE A SELF ANTIGEN.

8068
06:32:39,646 --> 06:32:40,546
AND THIS SHOULD BE WEAK.

8069
06:32:40,546 --> 06:32:41,848
DO WE SEE A DIFFERENCE?

8070
06:32:41,848 --> 06:32:42,782
THE ANSWER IS, YES.

8071
06:32:42,782 --> 06:32:45,385
YOU CAN SEE HERE THAT THE HER2 R

8072
06:32:45,385 --> 06:32:48,287
ALONE IS KILLING A HUGE NUMBER F

8073
06:32:48,287 --> 06:32:52,859
THE CELLS AND I DON'T KNOW WHY  

8074
06:32:52,859 --> 06:33:01,467
MY -- I CAN'T GET THIS TO WORK.

8075
06:33:01,467 --> 06:33:03,169
THAT IS THE DIFFERENCE AND DEPTF

8076
06:33:03,169 --> 06:33:03,703
THE HEALTHY TISSUE.

8077
06:33:03,703 --> 06:33:06,172
WHEN WE HAVE THE MIXED CAR WITHE

8078
06:33:06,172 --> 06:33:09,275
TCR, WE HAVE MUCH LEGS DEATH OFE

8079
06:33:09,275 --> 06:33:11,377
HEALTHY TISSUE AS COMPARED TO TE

8080
06:33:11,377 --> 06:33:17,150
HER2 CAR.

8081
06:33:17,150 --> 06:33:24,457
SO THEN -- WE DECIDED TO GIVE TS

8082
06:33:24,457 --> 06:33:27,860
A NAME AND SEE IF IT WOULD WORK

8083
06:33:27,860 --> 06:33:28,561
IN-VIVO SITUATION.

8084
06:33:28,561 --> 06:33:31,764
SO THIS IS CALLED AN AUTO

8085
06:33:31,764 --> 06:33:34,167
MUSEMERGENCY BREAKING SYSTEM.

8086
06:33:34,167 --> 06:33:34,500
ABS.

8087
06:33:34,500 --> 06:33:35,868
THE IDEA IS YOU'RE SEEING A

8088
06:33:35,868 --> 06:33:40,073
DIFFERENCE WHEN YOU HAVE SELF AD

8089
06:33:40,073 --> 06:33:42,675
THAT WHEN IT DETECTIVES SELF ITS

8090
06:33:42,675 --> 06:33:44,077
AUTONOMOUS BREAKING THE CAR

8091
06:33:44,077 --> 06:33:44,343
ACTIVITY.

8092
06:33:44,343 --> 06:33:46,079
SO NOW TO BE ABLE TO LOOK AT TH,

8093
06:33:46,079 --> 06:33:48,581
WE'RE USING A MODEL WHERE WE'RE

8094
06:33:48,581 --> 06:33:51,084
USING THE TUMOR WHICH HAS THE

8095
06:33:51,084 --> 06:33:54,287
NEO-ANTIGEN WITH HHAT AND HER2 D

8096
06:33:54,287 --> 06:33:56,689
HEALTHY TISSUE AND THE HEALTHY

8097
06:33:56,689 --> 06:33:58,458
TISSUE IS BIOLUMINESCENT.

8098
06:33:58,458 --> 06:34:01,294
AND THAT IS EXPRESSING WILDTYPE

8099
06:34:01,294 --> 06:34:03,463
HHAT AND ALSO EXPRESSING HER2.

8100
06:34:03,463 --> 06:34:06,399
SO THE QUESTION IS, DOES THIS WK

8101
06:34:06,399 --> 06:34:06,899
IN-VIVO?

8102
06:34:06,899 --> 06:34:08,501
BECAUSE OF LOTS -- THERE ARE LOS

8103
06:34:08,501 --> 06:34:10,703
OF THINGS THAT GO INTO THIS.

8104
06:34:10,703 --> 06:34:12,872
THERE IS A HUMAN SYSTEM IN MSG

8105
06:34:12,872 --> 06:34:13,473
MOUSE.

8106
06:34:13,473 --> 06:34:15,274
YOU HAVE TO WORK THROUGH THE

8107
06:34:15,274 --> 06:34:15,975
DIFFERENT LEVELS OF THE ANTIGENS

8108
06:34:15,975 --> 06:34:19,378
YOU HAVE AND THESE ARE EXPERIMES

8109
06:34:19,378 --> 06:34:20,780
THAT TOOK OVER EIGHT MONTHS TO T

8110
06:34:20,780 --> 06:34:21,180
WORKING.

8111
06:34:21,180 --> 06:34:22,482
WHAT YOU SEE HERE IS THAT IF WE

8112
06:34:22,482 --> 06:34:24,484
LOOK AT THE TUMOR, AND NOW WE'RE

8113
06:34:24,484 --> 06:34:26,285
LOOKING AT THE TUMOR GROWTH, UNL

8114
06:34:26,285 --> 06:34:29,188
YOU CAN SEE THAT BOTH THE HER2 R

8115
06:34:29,188 --> 06:34:31,824
AND OUR AEBS CAR ARE DOING A REY

8116
06:34:31,824 --> 06:34:34,093
GOOD JOB OF CONTROLLING TUMOR

8117
06:34:34,093 --> 06:34:34,393
GROWTH.

8118
06:34:34,393 --> 06:34:37,497
SO WHAT HAPPENS NOW IN TERMS OFE

8119
06:34:37,497 --> 06:34:38,397
HEALTHY TISSUE?

8120
06:34:38,397 --> 06:34:40,399
I WOULDN'T BE SHOWING YOU THIS F

8121
06:34:40,399 --> 06:34:44,003
IT DIDN'T WORK.

8122
06:34:44,003 --> 06:34:46,506
IN MOCK CELLS YOUR HEALTHY LUNG

8123
06:34:46,506 --> 06:34:49,308
TISSUE CONTINUES TO BE PRESENT D

8124
06:34:49,308 --> 06:34:51,911
YOUR HHAT IS PRESENTS.

8125
06:34:51,911 --> 06:34:54,113
BUT YOUR HER2 CAR HAS QUICKLY

8126
06:34:54,113 --> 06:34:55,815
WITHIN THREE DAYS KILLED OFF ALL

8127
06:34:55,815 --> 06:34:57,383
YOUR LUNG TISSUE IN THIS MOUSE.

8128
06:34:57,383 --> 06:34:59,418
NOW THIS IS TRANSPLANTED IN THE

8129
06:34:59,418 --> 06:35:03,122
MICE BUT THE MICE ARE STILL ALI.

8130
06:35:03,122 --> 06:35:05,124
BUT WHAT CAN YOU SEE HERE IS WHE

8131
06:35:05,124 --> 06:35:08,027
THE AEBS CAR IS HAVING SOME KILG

8132
06:35:08,027 --> 06:35:10,496
OF THE HEALTHY TISSUE, YOU HAVEY

8133
06:35:10,496 --> 06:35:12,999
MORE HERE THAN WHAT YOU HAVE INE

8134
06:35:12,999 --> 06:35:13,833
HER2 CAR.

8135
06:35:13,833 --> 06:35:16,803
SO HOPEFULLY IN LESS THAN 15

8136
06:35:16,803 --> 06:35:19,105
MINUTES I HAD I CONVINCED YOU WE

8137
06:35:19,105 --> 06:35:21,107
HAVE ANTAGONISM ENFORCED BREAKIG

8138
06:35:21,107 --> 06:35:23,142
SYSTEM WITH A CART T-CELL WE CAN

8139
06:35:23,142 --> 06:35:25,344
USE AS AN ACCELERATOR WHEN WE HE

8140
06:35:25,344 --> 06:35:27,213
A NEO-ANTIGEN AND A BREAK WHEN E

8141
06:35:27,213 --> 06:35:29,115
HAVE A TISSUE ANTIGEN AND THAT E

8142
06:35:29,115 --> 06:35:30,149
CAN THEREBY PROTECT.

8143
06:35:30,149 --> 06:35:32,218
SO THIS IS A REALLY NEW CONCEPTN

8144
06:35:32,218 --> 06:35:34,320
TERMS OF THINKING ABOUT HOW WE N

8145
06:35:34,320 --> 06:35:36,222
CONTROL THE RESPONSIVENESS WE WD

8146
06:35:36,222 --> 06:35:38,191
HAVE IN TERMS OF IMMUNOTHERAPY.

8147
06:35:38,191 --> 06:35:41,627
AND SO THIS IS A SLIDE THAT I

8148
06:35:41,627 --> 06:35:42,628
REALLY LIKE.

8149
06:35:42,628 --> 06:35:43,429
WHEN WE THINK ABOUT WHAT HAPPEND

8150
06:35:43,429 --> 06:35:46,732
IN 2002 AND LOTS OF REALLY

8151
06:35:46,732 --> 06:35:50,837
WONDERFUL PEOPLE WHO TRIED TO ME

8152
06:35:50,837 --> 06:35:51,437
THIS HAPPEN.

8153
06:35:51,437 --> 06:35:53,639
SOMEONE WHO I WORKED WITH IN ISL

8154
06:35:53,639 --> 06:35:58,344
IS REALLY RESPONSIBLE FOR A HUGE

8155
06:35:58,344 --> 06:36:01,280
AMOUNT OF THE WORK AND A SINGLE

8156
06:36:01,280 --> 06:36:02,782
CHIMERIC TCR BETA THING.

8157
06:36:02,782 --> 06:36:05,051
AND NOW WE'RE AT THE POINT OF

8158
06:36:05,051 --> 06:36:06,052
HAVING NEXT GENERATION CARS WHEE

8159
06:36:06,052 --> 06:36:08,221
WE WENT FROM DRIVING OUR CELLS O

8160
06:36:08,221 --> 06:36:09,989
BEING ABLE TO HAVE AUTONOMOUS

8161
06:36:09,989 --> 06:36:11,123
DRIVING AND I CERTAINLY DON'T TK

8162
06:36:11,123 --> 06:36:12,658
WE ARE QUITE THERE YET BUT

8163
06:36:12,658 --> 06:36:13,559
HOPEFULLY THIS IS SOMETHING THAS

8164
06:36:13,559 --> 06:36:16,829
IT A NEW WAY OF THINKING ABOUT

8165
06:36:16,829 --> 06:36:17,196
THIS.

8166
06:36:17,196 --> 06:36:18,965
AND SO BASICALLY THE IDEA IS THT

8167
06:36:18,965 --> 06:36:22,134
USING THE MATHEMATICAL MODELS WE

8168
06:36:22,134 --> 06:36:24,737
DEVELOPED, WE SHOWN YOU AND

8169
06:36:24,737 --> 06:36:27,139
CONVINCED YOU THAT CAR TCR DOEST

8170
06:36:27,139 --> 06:36:29,175
EXIST AND WE CAN PREDICT WHAT IS

8171
06:36:29,175 --> 06:36:31,644
GOING TO HAPPEN IN DIFFERENT

8172
06:36:31,644 --> 06:36:32,545
PERTURBATIONS -- I DIDN'T HAVE E

8173
06:36:32,545 --> 06:36:35,648
TO SHOW YOU THAT -- THIS ANTAGOM

8174
06:36:35,648 --> 06:36:37,049
SIGNIFICANTLY IMPACTS TUMOR

8175
06:36:37,049 --> 06:36:38,551
PROGRESSION IN BOTH LIQUID AND

8176
06:36:38,551 --> 06:36:40,286
SOLID TUMORS AND REALLY MOST

8177
06:36:40,286 --> 06:36:41,354
IMPORTANTLY, BECAUSE THIS IS WHE

8178
06:36:41,354 --> 06:36:43,055
THE FIELD HAD A LOT OF PROBLEMS.

8179
06:36:43,055 --> 06:36:46,959
THIS ANTAGONISM CONFERS COMPETIE

8180
06:36:46,959 --> 06:36:48,361
SURVIVAL ADVANTAGE FOR TUMORS

8181
06:36:48,361 --> 06:36:50,963
DURING WEAK TCR LYINGANCE AND

8182
06:36:50,963 --> 06:36:52,298
HETEROGENOUS TUMOR POPULATIONS.

8183
06:36:52,298 --> 06:36:54,667
AND THAT WE CAN USE THIS TO REDE

8184
06:36:54,667 --> 06:36:56,736
OFF TARGET TOXICITY AGAINST HEAY

8185
06:36:56,736 --> 06:36:56,969
TISSUE.

8186
06:36:56,969 --> 06:36:58,838
AND AS WE SAID BEFORE, THIS IS

8187
06:36:58,838 --> 06:37:01,274
REALLY A HUGE AMOUNT OF WORK WIH

8188
06:37:01,274 --> 06:37:03,309
INCREDIBLE AMOUNT OF COMPITATORY

8189
06:37:03,309 --> 06:37:04,744
BETWEEN THREE GROUPS WORKING ON

8190
06:37:04,744 --> 06:37:07,713
MODELING SIDE AND WORKING ON THE

8191
06:37:07,713 --> 06:37:09,649
MATHEMATICAL SIDE AND WORKING ON

8192
06:37:09,649 --> 06:37:10,883
THE BIOLOGICAL SIDE AND WORKING

8193
06:37:10,883 --> 06:37:12,952
WITH OUR CLINICAL COLLEAGUES AS

8194
06:37:12,952 --> 06:37:13,152
WELL.

8195
06:37:13,152 --> 06:37:14,987
WE WERE INCREDIBLY FORTUNATE TO

8196
06:37:14,987 --> 06:37:17,056
HAVE FLEX FUNDING FROM THE NCI O

8197
06:37:17,056 --> 06:37:19,492
REALLY BE ABLE TO CARRY THIS OUS

8198
06:37:19,492 --> 06:37:20,960
A SYNERGY GRANT AND SOMETHING TT

8199
06:37:20,960 --> 06:37:23,162
NONE OF US HAD BEEN WORKING ON

8200
06:37:23,162 --> 06:37:23,496
BEFORE.

8201
06:37:23,496 --> 06:37:25,998
AND SO I JUST WANTED TO SAY THAT

8202
06:37:25,998 --> 06:37:30,970
THERE A HUGE NUMBER OF PEOPLE FM

8203
06:37:30,970 --> 06:37:32,571
ALL THESE LABS WHO HAVE BEEN

8204
06:37:32,571 --> 06:37:33,572
INVOLVED IN ALL OF THIS.

8205
06:37:33,572 --> 06:37:35,374
AND I DIDN'T TALK ABOUT LOTS OF

8206
06:37:35,374 --> 06:37:39,378
STUFF GOING ON IN OUR LAB,

8207
06:37:39,378 --> 06:37:40,446
METABOLIC WORK.

8208
06:37:40,446 --> 06:37:41,881
BUT I'M FORTUNATE TO HAVE MOVED

8209
06:37:41,881 --> 06:37:44,984
HERE TO THE NIH TO HAVE STARTEDN

8210
06:37:44,984 --> 06:37:46,953
INCREDIBLE GROUP AND I'M GRATEFL

8211
06:37:46,953 --> 06:37:48,587
TO EVERYONE.

8212
06:37:48,587 --> 06:37:52,191
AND WE ALL STARTED WHERE WE CAME

8213
06:37:52,191 --> 06:37:53,793
FROM AND VALERIE IS HERE SO I

8214
06:37:53,793 --> 06:37:55,194
WANTED TO GIVE A SHOUT OUT.

8215
06:37:55,194 --> 06:37:57,096
I SPENT 20 PLUS YEARS IN FRANCED

8216
06:37:57,096 --> 06:37:58,698
EVERYTHING I DID, I LEARNED WITH

8217
06:37:58,698 --> 06:37:58,898
THEM.

8218
06:37:58,898 --> 06:38:01,801
SO I REALLY OWE THEM A HUGE DEBF

8219
06:38:01,801 --> 06:38:02,068
GRATITUDE.

8220
06:38:02,068 --> 06:38:02,668
SO THANK YOU.

8221
06:38:02,668 --> 06:38:10,276
[ APPLAUSE ]

8222
06:38:10,276 --> 06:38:14,847
>> SO WE HAVE TIME FOR
QUESTIONO

8223
06:38:14,847 --> 06:38:24,290
BOTH GREG AND NAOMI.

8224
06:38:24,290 --> 06:38:26,892
>> SO THIS IS REALLY
FASCINATING

8225
06:38:26,892 --> 06:38:27,693
WORK.

8226
06:38:27,693 --> 06:38:33,466
MY QUESTION IS, FOR SOME TUMORS.

8227
06:38:33,466 --> 06:38:36,235
>> [ INDISCERNIBLE ]

8228
06:38:36,235 --> 06:38:38,371
>> I THINK FOR THE TUMORS
THAT

8229
06:38:38,371 --> 06:38:41,207
MAYBE HAD NEW ANTIGEN, BUT AT TE

8230
06:38:41,207 --> 06:38:43,609
SAME TIME STILL EXPRESS THE

8231
06:38:43,609 --> 06:38:46,178
WILDTYPE ANTIGEN, HETEROZYGOUS

8232
06:38:46,178 --> 06:38:46,579
MUTATION.

8233
06:38:46,579 --> 06:38:52,885
WHAT IS GOING TO HAPPEN?

8234
06:38:52,885 --> 06:38:55,287
>> SO GREG HAS A SLIDE BUT
I THK

8235
06:38:55,287 --> 06:38:57,790
THE BOTTOM LINE WOULD BE THAT TE

8236
06:38:57,790 --> 06:39:00,693
HIGH TCR SIGNALING WOULD BE

8237
06:39:00,693 --> 06:39:02,595
DOMINANT OVER THE LOW TCR

8238
06:39:02,595 --> 06:39:02,862
SIGNALING.

8239
06:39:02,862 --> 06:39:05,398
WHAT IS REALLY INTERESTING AND

8240
06:39:05,398 --> 06:39:08,000
STRIKING WHEN YOU LOOK AT THE DA

8241
06:39:08,000 --> 06:39:12,405
AND I'M SURE DAREIO CAN TELL YOU

8242
06:39:12,405 --> 06:39:13,506
THIS AS WELL.

8243
06:39:13,506 --> 06:39:15,408
YOU SELECT FOR TCRs.

8244
06:39:15,408 --> 06:39:17,510
YOU'RE GETTING TCRs AND WHAT IS

8245
06:39:17,510 --> 06:39:18,544
INTERESTING FOR EXAMPLE, IF YOU

8246
06:39:18,544 --> 06:39:20,346
LOOK AT PATIENTS WHO GOT CARS AD

8247
06:39:20,346 --> 06:39:22,848
THEN THEY GET ANTI-PD-1 AND THEN

8248
06:39:22,848 --> 06:39:27,053
LOOK AT THE TCs AVAILABLE

8249
06:39:27,053 --> 06:39:28,354
AFTERWARDS, YOU DON'T HAVE THE

8250
06:39:28,354 --> 06:39:28,554
SAME.

8251
06:39:28,554 --> 06:39:33,726
YOU'RE SELECTING FOR STRONG TCR

8252
06:39:33,726 --> 06:39:35,261
ANTIGENS RATHER THAN FOR

8253
06:39:35,261 --> 06:39:36,729
ANTAGONISTIC SIGNAL.

8254
06:39:36,729 --> 06:39:38,030
THOSE WILL BE THE NEXT QUESTIONS

8255
06:39:38,030 --> 06:39:40,066
AND TO REALLY BE ABLE TO MODEL S

8256
06:39:40,066 --> 06:39:41,667
WITH THE PEOPLE HERE AND SAY, HW

8257
06:39:41,667 --> 06:39:44,036
DO WE LOOK AT TCR LIGAND STRENGH

8258
06:39:44,036 --> 06:39:46,939
AND THINK ABOUT THIS IN TERMS OA

8259
06:39:46,939 --> 06:39:48,674
CAR THERAPY WILL BE SOMETHING TT

8260
06:39:48,674 --> 06:39:54,780
IS INCREDIBLY EXCITING.

8261
06:39:54,780 --> 06:39:56,449
>> BASED ON THE MODEL WE
WANT TE

8262
06:39:56,449 --> 06:39:59,852
ABLE TO PREDICT FOR EVERYTHING

8263
06:39:59,852 --> 06:40:01,253
AGO - HOW FAR YOU ARE FROM THE L

8264
06:40:01,253 --> 06:40:05,491
WILL TELL YOU WHEREVER YOU ARE N

8265
06:40:05,491 --> 06:40:06,358
ANTAGONIST.

8266
06:40:06,358 --> 06:40:10,563
SO THE BIG PROBLEM IN CURRENT

8267
06:40:10,563 --> 06:40:12,531
MODELS -- THEY ASSUME BETTER

8268
06:40:12,531 --> 06:40:14,166
BIOPHYSICS THE MORE YOU ACTIVAT.

8269
06:40:14,166 --> 06:40:18,170
THERE IS NEGATIVE VAL I A YOU HE

8270
06:40:18,170 --> 06:40:24,543
TO PASS -- [ INAUDIBLE ]

8271
06:40:24,543 --> 06:40:28,047
MODELING IS REALLY CRITICAL.

8272
06:40:28,047 --> 06:40:32,651
>> MY QUESTION IS FOR
GREG.

8273
06:40:32,651 --> 06:40:36,355
IN YOUR -- THAT MODEL YOU HAD IN

8274
06:40:36,355 --> 06:40:41,260
LATENT SPACE OUTPUT PARAMETERS,T

8275
06:40:41,260 --> 06:40:44,163
YOU'RE TRAINING THEM WITH CYTOKE

8276
06:40:44,163 --> 06:40:45,264
SIGNALS YOU'RE MEASURING.

8277
06:40:45,264 --> 06:40:47,766
SO IF YOU EXTRACT THE FEATURE

8278
06:40:47,766 --> 06:40:50,169
WEIGHTS OF THOSE NEURONS COULD U

8279
06:40:50,169 --> 06:40:51,003
LEARN SOMETHING ABOUT THE

8280
06:40:51,003 --> 06:40:52,371
IMPORTANCE OF WHAT THESE CYTOKIS

8281
06:40:52,371 --> 06:40:52,571
ARE?

8282
06:40:52,571 --> 06:40:54,073
>> THAT'S THE BEAUTY OF
THESE

8283
06:40:54,073 --> 06:40:55,541
SIMPLE ENCODERS.

8284
06:40:55,541 --> 06:40:58,777
YOU CAN GO BACK AND ANALYZE EVEY

8285
06:40:58,777 --> 06:40:59,011
NEURON.

8286
06:40:59,011 --> 06:41:01,680
SO WE HAVE A BUNCH OF WEIGHT.

8287
06:41:01,680 --> 06:41:04,884
IF WE -- THAT'S WHAT YOU WOULD E

8288
06:41:04,884 --> 06:41:06,685
MONEY ON BECAUSE YOU HAVE A BUNH

8289
06:41:06,685 --> 06:41:10,389
OF THE WEIGHTS, AS YOU KNOW 0.5

8290
06:41:10,389 --> 06:41:14,693
INTERFERON GAMMA -- NONLINEAR

8291
06:41:14,693 --> 06:41:15,594
MANNER.

8292
06:41:15,594 --> 06:41:18,164
AND YOU CAN -- DISCOVER NEW STUF

8293
06:41:18,164 --> 06:41:23,068
WHICH IS IF YOUMENT TO MEASURE

8294
06:41:23,068 --> 06:41:24,470
ANTAGONISM VERY EARL WELLY ON.

8295
06:41:24,470 --> 06:41:27,306
IF YOU WANT TO MEASURE

8296
06:41:27,306 --> 06:41:28,407
RESPONSIVENESS WHAT YOU EXPECT,T

8297
06:41:28,407 --> 06:41:30,075
AGAIN WE CAN REALLY LOOK AT THIS

8298
06:41:30,075 --> 06:41:33,212
WEIGHT AND GO BACK TO -- IF YOU

8299
06:41:33,212 --> 06:41:36,081
TAKE AND YOU BUILD THESE CYTOKIS

8300
06:41:36,081 --> 06:41:40,186
YOU WILL BE ABLE TO --

8301
06:41:40,186 --> 06:41:41,387
IMMUNORESPONSE TO MORE ACTIVATIN

8302
06:41:41,387 --> 06:41:42,288
OR ANTAGONISM.

8303
06:41:42,288 --> 06:41:44,290
>> SO IN YOUR MODELS THEN,
THOSE

8304
06:41:44,290 --> 06:41:48,694
ARE THE HIGHEST WEIGHTS?

8305
06:41:48,694 --> 06:41:49,094
>> RIGHT.

8306
06:41:49,094 --> 06:41:51,297
SO FIRST STEPS WE WERE USING MOY

8307
06:41:51,297 --> 06:41:52,398
12 CYTOKINE PANEL.

8308
06:41:52,398 --> 06:41:54,500
NOW WE ARE 45.

8309
06:41:54,500 --> 06:41:56,602
YOU WOULD BE AMAZED STUFF WHICHS

8310
06:41:56,602 --> 06:41:58,003
NOT EXPRESSED.

8311
06:41:58,003 --> 06:42:00,105
CD8 MAKING IL17.

8312
06:42:00,105 --> 06:42:01,707
YOU WOULD NOT EXPECT THAT.

8313
06:42:01,707 --> 06:42:03,509
IT CAN BE VERY SIGNIFICANT IN TS

8314
06:42:03,509 --> 06:42:06,712
OF INFLAMMATION AND WE CAN DECIE

8315
06:42:06,712 --> 06:42:12,318
AND PRIORITIZE THINGS BASED ON E

8316
06:42:12,318 --> 06:42:12,551
WEIGHTS.

8317
06:42:12,551 --> 06:42:13,686
>> I THINK THIS IS
PROBABLY FOR

8318
06:42:13,686 --> 06:42:14,520
BOTH OF YOU.

8319
06:42:14,520 --> 06:42:16,589
BECAUSE IT REALLY HAS TO DO WITH

8320
06:42:16,589 --> 06:42:18,490
THE WAY THESE MODELS WORK.

8321
06:42:18,490 --> 06:42:20,926
THEY ARE STILL VERY TCH-BASED AD

8322
06:42:20,926 --> 06:42:22,494
WE SPENT A LOT OF TIME IN THE RT

8323
06:42:22,494 --> 06:42:24,597
OF THE LAST TWO DAYS TALKING ABT

8324
06:42:24,597 --> 06:42:27,099
THE DIFFERENCES IN THE CELL STAE

8325
06:42:27,099 --> 06:42:29,134
OF THE DIFFERENT T-CELL

8326
06:42:29,134 --> 06:42:29,435
POPULATIONS.

8327
06:42:29,435 --> 06:42:30,536
AND I'M ASSUMING THAT THEY ARE

8328
06:42:30,536 --> 06:42:33,105
GOING TOEL REALTER THE OPERATIOF

8329
06:42:33,105 --> 06:42:35,407
THE MODEL AND THE WEIGHTS OF THE

8330
06:42:35,407 --> 06:42:38,010
DIFFERENT SIGNAL FRANCE DEDUCTIN

8331
06:42:38,010 --> 06:42:39,511
PARAMETERS AND THE FEEDBACKS GIE

8332
06:42:39,511 --> 06:42:41,513
YOU THE NEGATIVE EFFECTS OF THE

8333
06:42:41,513 --> 06:42:43,082
LATENT SPACE TOO.

8334
06:42:43,082 --> 06:42:45,718
SO I GUESS -- OR A THIRD LATENT

8335
06:42:45,718 --> 06:42:46,919
SPACE WHICH MIGHT COME IN AS WE.

8336
06:42:46,919 --> 06:42:48,654
THAT THE IS SOMETHING THAT AS A

8337
06:42:48,654 --> 06:42:50,222
CAR-T CELL DESIGNER, YOU MIGHT E

8338
06:42:50,222 --> 06:42:50,923
ABLE TO PLAY WITH.

8339
06:42:50,923 --> 06:42:52,424
A LOT OF PEOPLE ARE TRYING TO PY

8340
06:42:52,424 --> 06:42:53,025
WITH IT.

8341
06:42:53,025 --> 06:42:55,060
SO I GUESS I WANTED TO JUST ASK

8342
06:42:55,060 --> 06:42:56,629
YOU, HOW YOU ARE THINKING ABOUT

8343
06:42:56,629 --> 06:43:00,432
THAT AND IS THERE WORK UNDERWAYO

8344
06:43:00,432 --> 06:43:05,938
SEE HOW ROBUST THESE ONE CELL SE

8345
06:43:05,938 --> 06:43:07,940
BUILT MODELS ARE AS YOU MOVE TO

8346
06:43:07,940 --> 06:43:10,409
OTHER KINDS OF T-CELLS, VIRTUAL

8347
06:43:10,409 --> 06:43:14,680
MEMORY, CD8 CELLS, NAIVE CD8 CE,

8348
06:43:14,680 --> 06:43:16,815
EXHAUSTIVE CD8 CELLS.

8349
06:43:16,815 --> 06:43:19,818
>> IT'S SOMETHING WE
THOUGHT A T

8350
06:43:19,818 --> 06:43:20,119
ABOUT.

8351
06:43:20,119 --> 06:43:22,721
I WOULD SAY THAT WE WERE PLEASAY

8352
06:43:22,721 --> 06:43:24,023
SURPRISED -- WE OBVIOUSLY STARTD

8353
06:43:24,023 --> 06:43:25,924
THESE EXPERIMENTS IN A MODEL OF

8354
06:43:25,924 --> 06:43:29,328
MICE WHERE ALL OF OUR T-CELLS WE

8355
06:43:29,328 --> 06:43:29,728
NAIVE.

8356
06:43:29,728 --> 06:43:31,330
WE DIDN'T HAVE TO PLAY WITH THE

8357
06:43:31,330 --> 06:43:31,530
TCR.

8358
06:43:31,530 --> 06:43:33,332
WE DIDN'T HAVE TO DO ANY

8359
06:43:33,332 --> 06:43:34,433
TRANSDUCTIONS AND THEN WE WENT O

8360
06:43:34,433 --> 06:43:35,701
HUMAN CELLS AND WE SAW SOMETHING

8361
06:43:35,701 --> 06:43:37,636
THAT WAS VERY SIMILAR.

8362
06:43:37,636 --> 06:43:39,171
SO I THINK IN TERMS OF MODELINGD

8363
06:43:39,171 --> 06:43:41,340
I THINK THAT ONE OF THE REASONSY

8364
06:43:41,340 --> 06:43:44,843
WE WERE ABLE TO -- SEEING A VERY

8365
06:43:44,843 --> 06:43:47,446
SIMILAR DIFFERENCE, AT LEAST ASE

8366
06:43:47,446 --> 06:43:48,647
STATE-OF-THE-ART IS TODAY FOR

8367
06:43:48,647 --> 06:43:51,750
THINGS LIKE CAR-T CELLS OR ADOPE

8368
06:43:51,750 --> 06:43:53,152
T-CELL THERAPIES, EVERYTHING IS

8369
06:43:53,152 --> 06:43:54,653
BEING ACTIVATED AND IT'S BEING

8370
06:43:54,653 --> 06:43:58,724
ACTIVATED IN A WAY THAT IS HUGEY

8371
06:43:58,724 --> 06:43:58,991
POWERFUL.

8372
06:43:58,991 --> 06:44:00,526
SO IF YOU WERE TAKING YOUR T-CEL

8373
06:44:00,526 --> 06:44:05,731
ALONE AND HAD YOUR CAR AND TCR N

8374
06:44:05,731 --> 06:44:07,232
IT, YOU WOULD HAVE HUGE DIFFERES

8375
06:44:07,232 --> 06:44:08,133
DEPENDING ON YOUR SUB SET.

8376
06:44:08,133 --> 06:44:10,669
WE ARE TAKING A TCR BEING

8377
06:44:10,669 --> 06:44:14,139
STIMULATED WITH CD3, CD28 AND I2

8378
06:44:14,139 --> 06:44:15,774
AND THEN SEEING WHAT IS HAPPENI.

8379
06:44:15,774 --> 06:44:17,042
BECAUSE OF THE FACT THAT WE HAVE

8380
06:44:17,042 --> 06:44:20,346
THAT UPSTREAM, WE ARE ACTUALLY

8381
06:44:20,346 --> 06:44:21,146
NEGATING THE DIFFERENCES BETWEEN

8382
06:44:21,146 --> 06:44:23,015
THE DIFFERENT SUBSETS.

8383
06:44:23,015 --> 06:44:24,149
THERE ARE GOING TO BE DIFFERENCS

8384
06:44:24,149 --> 06:44:24,783
AT SOME POINT.

8385
06:44:24,783 --> 06:44:26,552
ONE OF THE THINGS WE ARE SURPRID

8386
06:44:26,552 --> 06:44:29,755
AT IN THE LAB IS -- I THINK WE L

8387
06:44:29,755 --> 06:44:32,257
ASSUME WHEN WE LOOK AT T-CELLS M

8388
06:44:32,257 --> 06:44:34,560
PATIENTS WHO HAVE THE GO EN TONF

8389
06:44:34,560 --> 06:44:35,561
CHEMOTHERAPIES, THOSE WOULD BE E

8390
06:44:35,561 --> 06:44:38,797
T-CELLS THAT WOULD HAVE THE LEAT

8391
06:44:38,797 --> 06:44:40,566
RESPONSIVENESS WHEN WE LOOK AT

8392
06:44:40,566 --> 06:44:42,468
ANTI-TUMOR RESPONSES WHEN PUTTIG

8393
06:44:42,468 --> 06:44:43,502
IT IN TO SEE IT.

8394
06:44:43,502 --> 06:44:47,272
IN FACT, IT'S NOT THE PATIENT

8395
06:44:47,272 --> 06:44:48,540
T-CELLS THAT ARE THE WORST.

8396
06:44:48,540 --> 06:44:50,476
IT'S EVERY SINGLE DONOR IS

8397
06:44:50,476 --> 06:44:50,976
DIFFERENT.

8398
06:44:50,976 --> 06:44:53,178
PEOPLE WHO TELL YOU THEY DO A

8399
06:44:53,178 --> 06:44:53,946
EXPERIMENT WITH HUMAN CELLS 5 TS

8400
06:44:53,946 --> 06:44:57,082
AND WILL USING THE SAME DONOR

8401
06:44:57,082 --> 06:44:57,649
THAT'S CRAP.

8402
06:44:57,649 --> 06:44:59,385
BECAUSE -- SORRY.

8403
06:44:59,385 --> 06:45:00,252
THERE IS SO MANY TIMES WHEN PEOE

8404
06:45:00,252 --> 06:45:02,287
SAY THEY USE THE SAME BATCH OF

8405
06:45:02,287 --> 06:45:02,521
T-CELLS.

8406
06:45:02,521 --> 06:45:04,456
THEY ARE COMPLETELY DIFFERENT.

8407
06:45:04,456 --> 06:45:06,558
A HUGE DIFFERENCE IN ALL OF OUR

8408
06:45:06,558 --> 06:45:10,162
MAPS IS REALLY BASED ON DONORS.

8409
06:45:10,162 --> 06:45:12,798
SO THERE ARE HUGE DIFFERENCES TT

8410
06:45:12,798 --> 06:45:13,665
ARE DONOR BASED.

8411
06:45:13,665 --> 06:45:15,467
AND THAT'S SOMETHING WE NEED TO

8412
06:45:15,467 --> 06:45:18,871
SPEND MORE AND MORE TIME ON.

8413
06:45:18,871 --> 06:45:20,372
>> WHEN YOU BUILD THE
MODEL, ITS

8414
06:45:20,372 --> 06:45:23,041
THE BEAUTY OF COLLABORATION.

8415
06:45:23,041 --> 06:45:25,010
SO MANY DIFFERENT TYPES OF DONO,

8416
06:45:25,010 --> 06:45:28,380
SO MANY DIFFERENT TYPES OF TCR M

8417
06:45:28,380 --> 06:45:30,849
NEGATIVE MOUSE TO ALL THE WAY

8418
06:45:30,849 --> 06:45:32,684
EXHAUSTIVE AND EXPANDED CELLS, U

8419
06:45:32,684 --> 06:45:35,587
CAN STILL LEARN A MODEL WHICH IS

8420
06:45:35,587 --> 06:45:35,854
UNIVERSAL.

8421
06:45:35,854 --> 06:45:37,489
SO ALL CYTOKINES IF YOU LOOK AT

8422
06:45:37,489 --> 06:45:41,693
GAMMA AND IL-2, IT GOES FROM LIE

8423
06:45:41,693 --> 06:45:43,695
ONE TO 10 NANOMOLAR.

8424
06:45:43,695 --> 06:45:45,197
BECAUSE YOU CAN NORMALIZE IT WIH

8425
06:45:45,197 --> 06:45:48,600
ALL THE OTHER DIMENSIONS AND STL

8426
06:45:48,600 --> 06:45:50,803
LEARN THE WAY THE TCR IS WIRED,E

8427
06:45:50,803 --> 06:45:52,504
WAY THE CAR IS WIRED.

8428
06:45:52,504 --> 06:45:55,474
THAT'S WHY WE ARE GOING TO GO FM

8429
06:45:55,474 --> 06:45:57,876
MOUSE TO HUMANS IN A UNIVERSAL .

8430
06:45:57,876 --> 06:45:59,511
>> WE DON'T UNDERSTAND
ENOUGH

8431
06:45:59,511 --> 06:46:00,779
BECAUSE WITH GREG, WHAT WE HAVE

8432
06:46:00,779 --> 06:46:03,615
DONE AND AGAIN THIS IS UNPUBLIS,

8433
06:46:03,615 --> 06:46:05,584
BUT CRYSTAL AND RALEIGH SHAW ARE

8434
06:46:05,584 --> 06:46:08,487
BOTH RUNNING TRIALS OF THE SAME

8435
06:46:08,487 --> 06:46:09,488
CD22 CAR.

8436
06:46:09,488 --> 06:46:11,690
ONE IN STANFORD AND ONE NCI.

8437
06:46:11,690 --> 06:46:13,158
THE PATIENTS ARE DIFFERENT.

8438
06:46:13,158 --> 06:46:15,594
LOTS OF DIFFERENCES IN PEDIATRIC

8439
06:46:15,594 --> 06:46:16,829
POPULATION VERSUS ADULT.

8440
06:46:16,829 --> 06:46:18,397
WE COULD BLINDLY WITH GREG IN

8441
06:46:18,397 --> 06:46:19,898
TESTING THE SAMPLES, WE KNEW WHO

8442
06:46:19,898 --> 06:46:22,534
WAS TREATED AT STANFORD AND WHOS

8443
06:46:22,534 --> 06:46:24,102
TREATED AT THE NIH BECAUSE THE

8444
06:46:24,102 --> 06:46:25,404
MANUFACTURING WAS DIFFERENT.

8445
06:46:25,404 --> 06:46:28,607
NOW HOW THAT MANUFACTURING IS WL

8446
06:46:28,607 --> 06:46:31,310
PLAY INTO SOMETHING LIKE DAREIOS

8447
06:46:31,310 --> 06:46:33,412
CLINICAL TRIALS LOOKING AT LAG D

8448
06:46:33,412 --> 06:46:35,214
HOW THOSE CELLS ARE BEING USED

8449
06:46:35,214 --> 06:46:36,315
DIFFERENTLY IS SOMETHING THAT WL

8450
06:46:36,315 --> 06:46:37,516
BE FASCINATING.

8451
06:46:37,516 --> 06:46:39,284
BUT I COULD SHOW YOU THE DATA AD

8452
06:46:39,284 --> 06:46:41,119
YOU WOULD KNOW EXACTLY WHICH

8453
06:46:41,119 --> 06:46:42,120
PATIENT WAS WHERE.

8454
06:46:42,120 --> 06:46:45,324
>> THIS IS, I BELIEVE, A
QUESTIN

8455
06:46:45,324 --> 06:46:47,726
MORE FOR GREG.

8456
06:46:47,726 --> 06:46:50,829
YOU REDUCED THE RESPONSES DOWN O

8457
06:46:50,829 --> 06:46:53,198
SIX TYPES OF ANTIGENS AND WAS TT

8458
06:46:53,198 --> 06:46:58,403
JUST FOR THE OT1 SYSTEM OR

8459
06:46:58,403 --> 06:46:58,737
GENERALIZABLE?

8460
06:46:58,737 --> 06:47:01,306
IF YOU EXTENDED TO STUDIES, MORE

8461
06:47:01,306 --> 06:47:02,708
QUALITIES AND COULD YOU REDUCE

8462
06:47:02,708 --> 06:47:06,311
THOSE CATEGORIES TO IMMUNOSPEAK,

8463
06:47:06,311 --> 06:47:08,547
MEANING IS THERE ANTAGONIST TYPI

8464
06:47:08,547 --> 06:47:11,517
AND 2 WHICH MIGHT HAVE DIFFERENT

8465
06:47:11,517 --> 06:47:12,718
CYTOKINES OR SOMETHING THAT I CD

8466
06:47:12,718 --> 06:47:15,220
THEN PUT INTO CLUSTERS?

8467
06:47:15,220 --> 06:47:15,354
--

8468
06:47:15,354 --> 06:47:16,121
[ MULTIPLE SPEAKERS ]

8469
06:47:16,121 --> 06:47:18,423
>> THAT'S EXACTLY WHAT WE
ARE

8470
06:47:18,423 --> 06:47:19,424
DOING.

8471
06:47:19,424 --> 06:47:23,228
WE WANT TO DISCOVER MORE.

8472
06:47:23,228 --> 06:47:25,597
SO WE DO MORE SINGLE CELLS SO IS

8473
06:47:25,597 --> 06:47:26,832
NOT SIX CLASSES.

8474
06:47:26,832 --> 06:47:28,433
WE ARE MORE AT LIKE 12.

8475
06:47:28,433 --> 06:47:31,103
AND BEING ABLE TO ASSIGN WHICH

8476
06:47:31,103 --> 06:47:32,337
CLASS WILL BE THE CHALLENGE.

8477
06:47:32,337 --> 06:47:36,008
SO WHEN PEOPLE DO SINGLE CELL

8478
06:47:36,008 --> 06:47:37,643
RNA-SEQ AND -- THEY SEE EVERY CE

8479
06:47:37,643 --> 06:47:41,213
SEEMS TO BE ABLE TO GO INTO A OE

8480
06:47:41,213 --> 06:47:42,814
POT WHICH IS VERY DIFFERENT AND

8481
06:47:42,814 --> 06:47:44,149
BEING ABLE TO MAP THESE THINGS S

8482
06:47:44,149 --> 06:47:45,617
REALLY GOING TO BE THE CHALLENGE

8483
06:47:45,617 --> 06:47:48,820
BUT I THINK IT'S NOT JUST

8484
06:47:48,820 --> 06:47:49,121
ANTAGONIST.

8485
06:47:49,121 --> 06:47:51,657
WE ARE REALLY GOING TO DISPARATE

8486
06:47:51,657 --> 06:47:51,890
THINGS.

8487
06:47:51,890 --> 06:47:53,825
IF YOU WANT TO, YOU CAN HAVE A T

8488
06:47:53,825 --> 06:47:55,727
OF CLASSES AND AGAIN FOR THE

8489
06:47:55,727 --> 06:47:57,429
CLINICAL, I THINK IT WILL BE VEY

8490
06:47:57,429 --> 06:48:00,933
IMPORTANT BECAUSE IT CAUSES YOUO

8491
06:48:00,933 --> 06:48:04,236
REALLY PARSE RESPONSIBILITY IN A

8492
06:48:04,236 --> 06:48:05,437
BETTER WAY.

8493
06:48:05,437 --> 06:48:08,740
>> [ OFF MICROPHONE ]

8494
06:48:08,740 --> 06:48:09,274
>> WE DON'T WANT LAKES.

8495
06:48:09,274 --> 06:48:12,244
WE THINK IT'S A CONTINUOUS

8496
06:48:12,244 --> 06:48:12,511
CONTINUUM.

8497
06:48:12,511 --> 06:48:15,247
IF YOU GIVE ME A PCR, I CAN PUTT

8498
06:48:15,247 --> 06:48:17,549
IN PRECISE MANNER SO YOU CAN DEE

8499
06:48:17,549 --> 06:48:18,350
IT AS A CLASS.

8500
06:48:18,350 --> 06:48:22,054
WHEN YOU START TO DO A SINGLE

8501
06:48:22,054 --> 06:48:24,256
MUTANT AND THEN YOU CAN REALLY E

8502
06:48:24,256 --> 06:48:26,825
ABLE TO WORK ON IT.

8503
06:48:26,825 --> 06:48:29,094
>> YOU CAN EVEN MAYBE
CLASS 1,

8504
06:48:29,094 --> 06:48:32,598
CLASS 2 INDEPENDENT LIGAND.

8505
06:48:32,598 --> 06:48:33,665
>> THAT WAS BEAUTIFUL.

8506
06:48:33,665 --> 06:48:35,567
IN YOUR MODELS YOU'RE REALLY

8507
06:48:35,567 --> 06:48:38,570
FOCUSING ON SIGNALING TCR

8508
06:48:38,570 --> 06:48:38,837
SIGNALING.

8509
06:48:38,837 --> 06:48:40,872
AND GOING BACK TO OLD WORK OF

8510
06:48:40,872 --> 06:48:43,475
YOURS, GREG, JUST WONDERING IS

8511
06:48:43,475 --> 06:48:46,645
THERE A FEEDBACK TO THE CYTOKINE

8512
06:48:46,645 --> 06:48:47,245
SIGNALING ITSELF?

8513
06:48:47,245 --> 06:48:50,882
SO THAT THERE IS --

8514
06:48:50,882 --> 06:48:53,652
[ MULTIPLE SPEAKERS ]

8515
06:48:53,652 --> 06:48:56,054
>> RIGHT NOW WE ARE
MOTHERING

8516
06:48:56,054 --> 06:48:57,089
RIGOROUS ENGINEERING.

8517
06:48:57,089 --> 06:49:02,260
TAKE A CYTOKINE AND MAP BACK THE

8518
06:49:02,260 --> 06:49:02,427
TCR.

8519
06:49:02,427 --> 06:49:02,961
IT'S CONSISTENT.

8520
06:49:02,961 --> 06:49:04,763
IF YOU LOOK AT THE MODEL, IF WEE

8521
06:49:04,763 --> 06:49:06,565
ABLE TO MEASURE THINGS IN 10

8522
06:49:06,565 --> 06:49:07,766
MINUTES, WE COULD REALLY PREDICT

8523
06:49:07,766 --> 06:49:09,968
EXACTLY WHAT IS GOING TO HAPPENN

8524
06:49:09,968 --> 06:49:10,369
22 HOURS.

8525
06:49:10,369 --> 06:49:12,304
THERE IS A LOT OF REINFORCEMENT

8526
06:49:12,304 --> 06:49:15,073
FROM THE CYTOKINE BEING PRODUCE,

8527
06:49:15,073 --> 06:49:19,378
FEEDBACK ON TO THE TCR TO ENABLE

8528
06:49:19,378 --> 06:49:20,545
YOU TO BUILD THIS.

8529
06:49:20,545 --> 06:49:23,649
>> IN YOUR OLD DATA, ONE
WOULD

8530
06:49:23,649 --> 06:49:26,585
ARGUE THAT WEAK TCR SIGNALING WL

8531
06:49:26,585 --> 06:49:29,087
DESENSITIZE YOU TO CYTOKINE

8532
06:49:29,087 --> 06:49:30,088
SIGNALS --

8533
06:49:30,088 --> 06:49:31,990
[ MULTIPLE SPEAKERS ]

8534
06:49:31,990 --> 06:49:34,493
>> THE FACT THAT WEAK TCR
IN OTR

8535
06:49:34,493 --> 06:49:37,696
WORDS YOU TO SWITCH OFF -- QUICY

8536
06:49:37,696 --> 06:49:40,298
AND RAMP UP -- NOT GIVE YOU AS H

8537
06:49:40,298 --> 06:49:41,299
CONSUMPTION BECAUSE YOU DON'T HE

8538
06:49:41,299 --> 06:49:44,569
A LOT OF C25T WILL GIVE YOU A

8539
06:49:44,569 --> 06:49:45,971
DIFFERENT -- COMPARED TO STRONG

8540
06:49:45,971 --> 06:49:49,174
WHICH PRODUCES MORE CYTOKINE AND

8541
06:49:49,174 --> 06:49:50,709
CONSUMES MUST FASTER.

8542
06:49:50,709 --> 06:49:53,478
WE ARE BLIND TO THESE DIFFERENCS

8543
06:49:53,478 --> 06:49:55,113
BUT THAT'S WHAT THE MODEL LEARN.

8544
06:49:55,113 --> 06:49:58,183
SO I'M NOT ABLE TO TELL YOU EXAY

8545
06:49:58,183 --> 06:49:59,885
WHICH KINASE IS DOING IT, BUT WE

8546
06:49:59,885 --> 06:50:02,688
CAN SEE IT FROM THE DATA.

8547
06:50:02,688 --> 06:50:06,191
TO BUILD THE DIFFERENT -- WE CAN

8548
06:50:06,191 --> 06:50:06,692
USE --

8549
06:50:06,692 --> 06:50:09,795
>> BUT AMAZINGLY, EVERY
CENTER S

8550
06:50:09,795 --> 06:50:11,296
DOING THEIR OWN DIFFERENT CYTOKS

8551
06:50:11,296 --> 06:50:13,965
WHEN THEY ARE MAKING T-CELLS FOR

8552
06:50:13,965 --> 06:50:14,599
ADOPTIVE TRANSFER.

8553
06:50:14,599 --> 06:50:17,569
WHAT WE ARE CONVINCED OF, WHAT L

8554
06:50:17,569 --> 06:50:19,404
TAKE A LONG TIME TO FIGURE OUT,W

8555
06:50:19,404 --> 06:50:22,307
ARE YOU CHANGING THE TCR CAR

8556
06:50:22,307 --> 06:50:24,409
BALANCE IF YOU'RE MAKING YOUR CS

8557
06:50:24,409 --> 06:50:27,112
WITH IL7 OR IL15 VERSUS MAKING M

8558
06:50:27,112 --> 06:50:28,013
WITH IL-2.

8559
06:50:28,013 --> 06:50:30,382
AND YOU'RE GOING TO BE SELECTING

8560
06:50:30,382 --> 06:50:32,484
OUT DIFFERENCES IN TERMS OF THA.

8561
06:50:32,484 --> 06:50:34,186
I DON'T THINK IT'S A QUESTION OF

8562
06:50:34,186 --> 06:50:35,153
DIVERSITY, PER SE BUT YOU PROBAY

8563
06:50:35,153 --> 06:50:36,288
WILL BE SEEING DIFFERENCES IN TS

8564
06:50:36,288 --> 06:50:39,491
OF WHAT YOU'RE SEEING FOR ANT JN

8565
06:50:39,491 --> 06:50:40,792
INTERACTIONS.

8566
06:50:40,792 --> 06:50:45,430
AND ESPECIALLY FOR LIQUID TUMORS

8567
06:50:45,430 --> 06:50:48,700
WHERE THE CAR TARGET IS NOT

8568
06:50:48,700 --> 06:50:50,802
PRESENT, THAT'S GOING TO BE EASR

8569
06:50:50,802 --> 06:50:52,804
TO DEAL WITH BUT WITH SOLID TUMS

8570
06:50:52,804 --> 06:50:55,607
WHERE YOU WILL HAVE THE INTERACN

8571
06:50:55,607 --> 06:50:56,408
T WILL BE MORE INTERESTING.

8572
06:50:56,408 --> 06:50:58,410
I DON'T THINK WE ARE OUT OF A JB

8573
06:50:58,410 --> 06:51:05,183
ANY TIME SOON.

8574
06:51:05,183 --> 06:51:05,684
>> [ OFF MICROPHONE ]

8575
06:51:05,684 --> 06:51:06,084
>> THANK YOU.

8576
06:51:06,084 --> 06:51:14,292
[ APPLAUSE ]

8577
06:51:14,292 --> 06:51:15,393
>> YOU MADE IT TO THE END.

8578
06:51:15,393 --> 06:51:17,462
WE MADE IT TO THE END.

8579
06:51:17,462 --> 06:51:20,999
WE REALLY JUST WANTED TO THANK .

8580
06:51:20,999 --> 06:51:21,700
JEN WHERE ARE YOU?

8581
06:51:21,700 --> 06:51:24,136
YOU WANT TO SAY SOMETHING?

8582
06:51:24,136 --> 06:51:30,308
COME SAY SOMETHING.

8583
06:51:30,308 --> 06:51:33,111
IT'S REALLY BEEN A HUGE PLEASUR.

8584
06:51:33,111 --> 06:51:37,015
THIS IS THE FIRST TIME WE'VE HAD

8585
06:51:37,015 --> 06:51:39,117
THE BASIC IMMUNOLOGY MEETING SIE

8586
06:51:39,117 --> 06:51:39,417
COVID.

8587
06:51:39,417 --> 06:51:40,552
IT'S SUCH A PLEASURE TO SEE PEOE

8588
06:51:40,552 --> 06:51:42,320
WHO ARE HERE IN PERSON.

8589
06:51:42,320 --> 06:51:45,390
WE REALLY WANTED TO COME AND SAY

8590
06:51:45,390 --> 06:51:48,026
THAT PLEASE DO TELL YOUR FRIEND,

8591
06:51:48,026 --> 06:51:49,227
YOUR NEIGHBORS, YOUR PEN PALS

8592
06:51:49,227 --> 06:51:51,129
ACROSS THE WORLD, THESE ARE FREE

8593
06:51:51,129 --> 06:51:51,396
MEETINGS.

8594
06:51:51,396 --> 06:51:53,298
WE REALLY WANT TO BE ABLE TO REH

8595
06:51:53,298 --> 06:51:55,400
PEOPLE WHO CAN'T GO TO MEETINGSD

8596
06:51:55,400 --> 06:51:56,501
MONTH CAN BENEFIT FROM TWO DAYS.

8597
06:51:56,501 --> 06:51:57,602
SO SEND IT TO THEM.

8598
06:51:57,602 --> 06:52:05,877
AND THEN THE NEXT MEETING WILL A

8599
06:52:05,877 --> 06:52:08,914
CELEBRATION OF 50 YEARS OF STEVE

8600
06:52:08,914 --> 06:52:11,216
ROSENBERG AT THE NCI.

8601
06:52:11,216 --> 06:52:13,185
IT WILL ALSO BE A FREE MEETING.

8602
06:52:13,185 --> 06:52:15,320
IT WILL ALSO BE BEFORE OCTOBER .

8603
06:52:15,320 --> 06:52:17,823
THERE IS A REASON WHY THAT HAPPS

8604
06:52:17,823 --> 06:52:19,724
FOR THOSE OF YOU WHO CAN GUESS.

8605
06:52:19,724 --> 06:52:21,827
AGAIN, IT'S REALLY A HUGE PLEASE

8606
06:52:21,827 --> 06:52:25,330
AND I'LL LET JIM FINISH.

8607
06:52:25,330 --> 06:52:27,499
>> MY LAST WORD IS, THANK
YOU

8608
06:52:27,499 --> 06:52:28,700
EVERYONE FOR YOUR QUESTIONS.

8609
06:52:28,700 --> 06:52:31,736
THANK YOU FOR YOUR PARTICIPATIO.

8610
06:52:31,736 --> 06:52:33,238
THIS IS ALL COMING FROM YOU GUYS

8611
06:52:33,238 --> 06:52:39,044
AND I HAVE TO SAY ABOUT 1000

8612
06:52:39,044 --> 06:52:39,911
REGISTRANTS, SOME JUST CAME IN.

8613
06:52:39,911 --> 06:52:43,114
WE HAD OVER THE TIME, CONTINUOUS

8614
06:52:43,114 --> 06:52:44,749
TWO50 PEOPLE ALWAYS ATTENDING ON

8615
06:52:44,749 --> 06:52:45,350
LINE.

8616
06:52:45,350 --> 06:52:47,953
SO THIS WAS IN MY VIEW, A HUGE

8617
06:52:47,953 --> 06:52:48,253
SUCCESS.

8618
06:52:48,253 --> 06:52:52,057
WE BEAT COVID.

8619
06:52:52,057 --> 06:52:54,759
WE BEAT -- FOR ALL THE SPEAKERSO

8620
06:52:54,759 --> 06:52:57,162
CAME, I JUST HAVE TO SAY THANK U

8621
06:52:57,162 --> 06:53:00,131
AND THEN, NAOMI GAVE EVERYONE A

8622
06:53:00,131 --> 06:53:01,433
CREDIT EXCEPT FOR HERSELF, SO I

8623
06:53:01,433 --> 06:53:04,236
WANT TO SAY THANK YOU, NAOMI FOR

8624
06:53:04,236 --> 06:53:07,706
LEADING THIS ONE.

8625
06:53:07,706 --> 06:53:09,841
[ APPLAUSE ]

8626
06:53:09,841 --> 06:53:12,043
AND THE NEXT MEETING FOR THIS BC

8627
06:53:12,043 --> 06:53:13,044
IMMUNOLOGY WILL BE IN THREE YEAS

8628
06:53:13,044 --> 06:53:16,815
AND I'M VERY SURE THAT I'M NOT

8629
06:53:16,815 --> 06:53:17,549
GOING TOL CHAIR BUT SOMEBODY ELE

8630
06:53:17,549 --> 06:53:17,749
WILL.

8631
06:53:17,749 --> 06:53:20,552
THANK YOU AND HAVE A GOOD NIGHT.

8632
06:53:20,552 --> 06:53:21,653
>> AND GIVE YOURSELF A
HAND.

8633
06:53:21,653 --> 06:53:31,653
THANK YOU.