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Duration of antigen receptor signaling determines T-cell tolerance or activation.


ABSTRACT: The early events that determine the decision between lymphocyte tolerance and activation are not well-understood. Using a model of systemic self-antigen recognition by CD4(+) T cells, we show, using single-cell biochemical analyses, that tolerance is characterized by transient signaling events downstream of T-cell receptor engagement in the mammalian target of rapamycin (mTOR) and NF-?B pathways. Parallel studies done by live cell imaging show that the key difference between tolerance and activation is the duration of the T cell-antigen presenting cell (APC) interaction, as revealed by stable T-cell immobilization on antigen encounter. Brief T cell-APC interactions result in tolerance, and prolonged interactions are associated with activation and the development of effector cells. These studies show that the duration of T cell-APC interactions and magnitude of associated TCR-mediated signaling are key determinants of lymphocyte tolerance vs. activation.

SUBMITTER: Katzman SD 

PROVIDER: S-EPMC2964228 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Duration of antigen receptor signaling determines T-cell tolerance or activation.

Katzman Shoshana D SD   O'Gorman William E WE   Villarino Alejandro V AV   Gallo Eugenio E   Friedman Rachel S RS   Krummel Matthew F MF   Nolan Garry P GP   Abbas Abul K AK  

Proceedings of the National Academy of Sciences of the United States of America 20101004 42


The early events that determine the decision between lymphocyte tolerance and activation are not well-understood. Using a model of systemic self-antigen recognition by CD4(+) T cells, we show, using single-cell biochemical analyses, that tolerance is characterized by transient signaling events downstream of T-cell receptor engagement in the mammalian target of rapamycin (mTOR) and NF-κB pathways. Parallel studies done by live cell imaging show that the key difference between tolerance and activa  ...[more]

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