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

Shoshana D. Katzman, William E. O'Gorman, Alejandro V. Villarino, Eugenio Gallo, Rachel S. Friedman, Matthew F. Krummel, Garry P. Nolan, Abul K. Abbas

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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-κB 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.

Original languageEnglish (US)
Pages (from-to)18085-18090
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number42
DOIs
StatePublished - Oct 19 2010
Externally publishedYes

Keywords

  • Autoimmunity
  • CD4 T cell
  • Lymphopenia

ASJC Scopus subject areas

  • General

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