Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection.
Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection.
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DOI：
10.1084/jem.20021698
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发表时间：
2003-02-03
影响因子：
15.3
通讯作者：
Bosselut, R
中科院分区：
文献类型：
--
作者：
Liu, XL;Adams, A;Wildt, KF;Aronow, B;Feigenbaum, L;Bosselut, R
虽然T细胞受体(TCR)信号对于胸腺内T细胞阳性选择是必不可少的，但它们是否只用于启动这一过程，或者是否整个过程都需要它们来促进胸腺细胞的分化和存活，仍然存在争议。为了解决这个问题，我们设计了一种新的方法，在体内以发育阶段特异性的方式干扰胸腺细胞TCR信号。我们重组了缺乏ZAP70的小鼠，ZAP70是TCR信号传递所需的一种酪氨酸激酶，在T细胞发育过程中正常表达，由腺苷脱氨酶(ADA)基因增强子驱动的ZAP70转基因，该基因在CD4+CD8+胸腺细胞中活跃，但在CD4+或CD8+单一阳性(SP)胸腺细胞中不活跃。在这类小鼠中，ZAP70表达的终止损害了TCR信号转导，并在阳性选择开始后但在完成之前阻止了胸腺细胞的发育。停滞的胸腺细胞终止RAG基因表达，上调TcR和Bcl2的表达，但不能分化为成熟的CD4SP或CD8SP胸腺细胞，可通过疏忽挽救死亡或维持白细胞介素7Rα的表达。这些观察确定了一种依赖于TCR的校对机制，该机制在完成阳性选择之前验证胸腺细胞TCR的特异性和分化选择。
Although T cell receptor (TCR) signals are essential for intrathymic T cell–positive selection, it remains controversial whether they only serve to initiate this process, or whether they are required throughout to promote thymocyte differentiation and survival. To address this issue, we have devised a novel approach to interfere with thymocyte TCR signaling in a developmental stage-specific manner in vivo. We have reconstituted mice deficient for Zap70, a tyrosine kinase required for TCR signaling and normally expressed throughout T cell development, with a Zap70 transgene driven by the adenosine deaminase (ADA) gene enhancer, which is active in CD4+CD8+ thymocytes but inactive in CD4+ or CD8+ single-positive (SP) thymocytes. In such mice, termination of Zap70 expression impaired TCR signal transduction and arrested thymocyte development after the initiation, but before the completion, of positive selection. Arrested thymocytes had terminated Rag gene expression and up-regulated TCR and Bcl-2 expression, but failed to differentiate into mature CD4 or CD8 SP thymocytes, to be rescued from death by neglect or to sustain interleukin 7Rα expression. These observations identify a TCR-dependent proofreading mechanism that verifies thymocyte TCR specificity and differentiation choices before the completion of positive selection.
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影响因子：
5.3
作者：
GAUEN, LKT;ZHU, YX;SHAW, AS
通讯作者：
SHAW, AS
影响因子：
15.3
作者：
GUIDOS, CJ;DANSKA, JS;WEISSMAN, IL
通讯作者：
WEISSMAN, IL
DOI：
10.1084/jem.194.4.507
发表时间：
2001-08-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gong Q;Jin X;Akk AM;Foger N;White M;Gong G;Bubeck Wardenburg J;Chan AC
通讯作者：
Chan AC
影响因子：
--
作者：
FOWLKES, BJ;PARDOLL, DM
通讯作者：
PARDOLL, DM
影响因子：
64.5
作者：
Akashi, K;Kondo, M;Weissman, IL
通讯作者：
Weissman, IL