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Creating Super-regulatory T Lymphocytes

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Air date: Wednesday, February 24, 2010, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
Views: Total views: 175 * This only includes stats from October 2011 and forward.
Category: WALS - Wednesday Afternoon Lectures
Runtime: 01:03:01
Description: The power of the adaptive immune system is checked by regulatory T lymphocytes to prevent autoimmunity and immunopathology. In the absence of regulatory T cells humans and mice suffer fatal, multiorgan autoimmunity. Regulatory T cells function by a cell-cell contact dependent suppression of other T lymphocyte’s proliferation and effector mechanisms. All T lymphocytes, regulatory and effector, rely on cell-cell junctions for recognition of self and foreign peptides bound to major histocompatibility complex (MHC) proteins that call T cells to action. These immunologically specific cell-cell junctions are described as immunological synapses.

The immunological synapse is a stable cell-cell junction based on turning the motile machinery to the T cell inward to create a “bull’s eye” structure that efficiently gathers MHC-peptide complexes to sustain signaling in an integrin dependent manner. We have compared the immunological synapse of regulatory and adaptive T cells and found a remarkable divergence between the two otherwise similar appearing structures. In effector T cells the mechanoregulatory enzyme PKC-q is polarized toward the immunological synapse, whereas in regulatory T cells the enzyme is excluded from the immunological synapse and is concentrated in the pole of the cell farthest from the synapse- the distal pole. While inhibition of PKC-q in effector T cells blocks proliferation and cytokine production, inhibition of PKC-q in regulatory T cells increases their suppressive activity.

We further found that inhibition of PKC-q can reverse defective activity of regulatory T cells from patients with rheumatoid arthritis (RA). Along these lines, treatment of regulatory T cells with tumor necrosis factor (TNF), a critical pathogenic cytokine in RA, abrogates regulatory T cell activity, apparently by re-polarizing PKC-q to the immunological synapse. PKC-q inhibition restored activity in TNFa treated regulatory T cells. Pretreatment of regulatory T cells with a PKC-q inhibitor improved their in vivo suppression of colitis in a mouse model. We conclude that T cell receptor activated PKC-q mediates negative feedback on regulatory T cell activity and abrogating this feedback pathways results in “super” regulatory T cells with potential for treating autoimmune disease and immunopathology.

The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.
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NLM Title: Creating super-regulatory T lymphocytes / Michael Dustin.
Author: Dustin, Mike.
National Institutes of Health (U.S.)
Publisher:
Abstract: (CIT): The power of the adaptive immune system is checked by regulatory T lymphocytes to prevent autoimmunity and immunopathology. In the absence of regulatory T cells humans and mice suffer fatal, multiorgan autoimmunity. Regulatory T cells function by a cell-cell contact dependent suppression of other T lymphocyte"s proliferation and effector mechanisms. All T lymphocytes, regulatory and effector, rely on cell-cell junctions for recognition of self and foreign peptides bound to major histocompatibility complex (MHC) proteins that call T cells to action. These immunologically specific cell-cell junctions are described as immunological synapses. The immunological synapse is a stable cell-cell junction based on turning the motile machinery to the T cell inward to create a "bull"s eye" structure that efficiently gathers MHC-peptide complexes to sustain signaling in an integrin dependent manner. We have compared the immunological synapse of regulatory and adaptive T cells and found a remarkable divergence between the two otherwise similar appearing structures. In effector T cells the mechanoregulatory enzyme PKC-q is polarized toward the immunological synapse, whereas in regulatory T cells the enzyme is excluded from the immunological synapse and is concentrated in the pole of the cell farthest from the synapse- the distal pole. While inhibition of PKC-q in effector T cells blocks proliferation and cytokine production, inhibition of PKC-q in regulatory T cells increases their suppressive activity. We further found that inhibition of PKC-q can reverse defective activity of regulatory T cells from patients with rheumatoid arthritis (RA). Along these lines, treatment of regulatory T cells with tumor necrosis factor (TNF), a critical pathogenic cytokine in RA, abrogates regulatory T cell activity, apparently by re-polarizing PKC-q to the immunological synapse. PKC-q inhibition restored activity in TNFa treated regulatory T cells. Pretreatment of regulatory T cells with a PKC-q inhibitor improved their in vivo suppression of colitis in a mouse model. We conclude that T cell receptor activated PKC-q mediates negative feedback on regulatory T cell activity and abrogating this feedback pathways results in "super" regulatory T cells with potential for treating autoimmune disease and immunopathology. The NIH Director's Wednesday Afternoon Lecture Series includes weekly scientific talks by some of the top researchers in the biomedical sciences worldwide.
Subjects: T-Lymphocytes, Regulatory--immunology
Publication Types: Lectures
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NLM Classification: QW 568
NLM ID: 101525669
CIT Live ID: 8237
Permanent link: https://videocast.nih.gov/launch.asp?15645

 

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