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

被引:55
作者
Katzman, Shoshana D. [1 ]
O'Gorman, William E. [2 ]
Villarino, Alejandro V. [1 ]
Gallo, Eugenio [1 ]
Friedman, Rachel S. [1 ]
Krummel, Matthew F. [1 ]
Nolan, Garry P. [2 ]
Abbas, Abul K. [1 ]
机构
[1] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA
[2] Stanford Univ, Baxter Lab Genet Pharmacol, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
autoimmunity; CD4 T cell; lymphopenia; PROTEIN S6 PHOSPHORYLATION; DENDRITIC CELLS; LYMPH-NODES; IN-VIVO; MAMMALIAN TARGET; LYMPHOCYTES; RESPONSES; RAPAMYCIN; PATHWAYS; DYNAMICS;
D O I
10.1073/pnas.1010560107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-kappa 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 cellAPC 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.
引用
收藏
页码:18085 / 18090
页数:6
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