A sharp T-cell antigen receptor signaling threshold for T-cell proliferation

被引:116
作者
Au-Yeung, Byron B. [1 ]
Zikherman, Julie [1 ]
Mueller, James L. [1 ]
Ashouri, Judith F. [1 ]
Matloubian, Mehrdad [1 ]
Cheng, Debra A. [1 ]
Chen, Yiling [1 ]
Shokat, Kevan M. [2 ,3 ]
Weiss, Arthur [1 ,3 ]
机构
[1] Univ Calif San Francisco, Dept Med, Div Rheumatol, Rosalind Russell & Ephraim P Engleman Arthrit Res, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA
基金
新加坡国家研究基金会; 美国国家卫生研究院;
关键词
CLONAL EXPANSION; CUTTING EDGE; DIFFERENTIAL REQUIREMENTS; CATALYTIC-ACTIVITY; TRANSGENIC MICE; IN-VIVO; CD4(+); NAIVE; ACTIVATION; RESPONSES;
D O I
10.1073/pnas.1413726111
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
T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77-eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery.
引用
收藏
页码:E3679 / E3688
页数:10
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