Dr. Sharpe's laboratory is interested in analyzing the role of costimulatory molecules in T cell activation in vivo. Costimulation is a pivotal event for T cell activation, determining the functional outcome of T cell interaction with antigen presenting cells (activation versus anergy). Her laboratory's work has focused on the obligatory in vivo role of costimulators using targeted gene disruption and have revealed striking and unexpected functions of costimulatory pathways. Analysis of B7-1 deficient mice provided the first evidence for the existence of additional functional CD28/CTLA-4 counter-receptors in vivo. As a result of these findings, a second CTLA-4 counter-receptor, B7-2, was cloned and revealed as the major early activating costimulator in this pathway. Mice lacking both B7-1 and B7-2 exhibit profound immunologic deficits. Together, these 3 B7 deficient strains have facilitated a comparative analysis of the in vivo functions of B7-1 and B7-2, as well as definitive tools for determining when the B7:CD28/CTLA-4 pathway is essential for T cell activation. Her CTLA-4 deficient mouse revealed a critical role for CTLA-4 in turning off activated T cells. This critical negative immunoregulatory function of CTLA-4 provides a previously unsuspected means by which costimulation can regulate responses to self antigens and potentially offers new approaches for manipulating activated T cells. More recently, she has studied the functions of newly discovered members of the B7-CD28 superfamily (ICOS:B7h and PD-1:PD-L1/PD-L2 pathways) and helped identify the P-D-1:PD-L1 pair as playing a key inhibitory role in immune suppression during chronic viral infection. Her talk today will focus on the role of PD-1 and its ligands in regulating T cell activation and tolerance, as well as the new PD-L1:B7-1 pathway.

Dr. Sharpe received her BA from Radcliffe College and her MD and PhD from Harvard Medical School where she worked with Dr. Bernie Fields on the genetics of reovirus replication. After a residency in pathology at Brigham and Women's Hospital, she worked with Dr. Rudi Jaenisch on pioneering studies of retroviral infection of embryos, as well as studies of induction of spongiform neurodegeneration by the Cas-Br-E retrovirus. Her training in mouse embryology and the use of embryonic stem cells strongly influenced the work in her own laboratory, where her studies have concentrated on the analysis of lymphocyte function in vivo using transgenic and 'knockout' mice. Dr. Sharpe's laboratory is a leader in the area of costimulation, a critical process in T cell activation that determines the functional outcome (activation versus anergy) of T cells after interaction with antigen presenting cells.

Dr. Sharpe is considered a world expert on costimulatory molecules and immune function. Her animals studies have played a central role in defining the in vivo physiological role of these molecules and the mice she has generated have been a key resource to the entire field, especially investigators examining the role of these pathways in diverse pathologic states. Her primary publications have appeared in high profile journals and her reviews are the standards in the field.

Dr. Sharpe is the George Fabyan Professor of Comparative Pathology at Harvard Medical School, the Director of the Immunology Research Division of the Brigham and Women's Hospital and the Vice-chair for Education in the Department of Pathology at Harvard Medical School. She was the recipient of the 2006 Distinguished Lecturer Award from the American Association of Immunologists and was elected to the American Academy of Arts and Sciences in 2007.

http://www.dfhcc.harvard.edu/membership/member-profile/member/321/0

The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.