Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development

被引：53

作者：

Au-Yeung, Byron B. ^{[1
,2
,3
,4
]}

Melichar, Heather J. ^{[5
]}

Ross, Jenny O. ^{[5
]}

Cheng, Debra A. ^{[1
,2
,3
,4
]}

Zikherman, Julie ^{[1
,2
,3
,4
]}

Shokat, Kevan M. ^{[1
,6
]}

Robey, Ellen A. ^{[5
]}

Weiss, Arthur ^{[1
,2
,3
,4
]}

机构：

[1] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[4] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[5] Univ Calif Berkeley, Dept Mol & Cell Biol, Div Immunol & Pathogenesis, Berkeley, CA 94720 USA

[6] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

来源：

NATURE IMMUNOLOGY | 2014年 / 15卷 / 07期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

POSITIVE SELECTION; NEGATIVE SELECTION; TYROSINE KINASE; RECEPTOR; ZAP-70; EXPRESSION; SYK; INHIBITOR; FAMILY; LCK;

D O I：

10.1038/ni.2918

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

The catalytic activity of Zap70 is crucial for T cell antigen receptor (TCR) signaling, but the quantitative and temporal requirements for its function in thymocyte development are not known. Using a chemical-genetic system to selectively and reversibly inhibit Zap70 catalytic activity in a model of synchronized thymic selection, we showed that CD4(+)CD8(+) thymocytes integrate multiple, transient, Zap70-dependent signals over more than 36 h to reach a cumulative threshold for positive selection, whereas 1 h of signaling was sufficient for negative selection. Titration of Zap70 activity resulted in graded reductions in positive and negative selection but did not decrease the cumulative TCR signals integrated by positively selected OT-I cells, which revealed heterogeneity, even among CD4(+)CD8(+) thymocytes expressing identical TCRs undergoing positive selection.

引用

页码：687 / 694

页数：8

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