Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages.
Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages.
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DOI：
10.4049/jimmunol.1303085
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发表时间：
2014-06-01
期刊：
影响因子：
--
通讯作者：
Seddon B
中科院分区：
文献类型：
--
作者：
Sinclair C;Seddon B
T细胞受体（TCR）信号在胸腺细胞的发育命运中起着重要作用。目前的模型表明TCR信号持续时间指导CD4与CD8谱系发育。为了直接研究TCR信号传导在阳性选择过程中的作用，我们在一组选择性胸腺细胞中关闭了信号传导，并及时跟踪了它们随后的命运。我们使用可诱导的Zap70转基因小鼠模型来实现这一点，该模型允许Zap70依赖性信号被打开，然后再次关闭。令人惊讶的是，CD4+ CD810胸腺细胞中TCR信号传导的丧失并不阻止它们发育为定向CD4单阳性（SP），也不阻止它们继续成熟为HSA10SP。然而，CD4SP的数量经历了一个实质性的下降后Zap70表达的损失，这表明激酶的重要生存作用。TCR信号传导的终止被认为是CD8谱系发育中的重要步骤。然而，Zap70表达的缺失导致CD8谱系前体胸腺细胞的快速死亡和不能产生CD8 SP。值得注意的是，延长窗口Zap70表达足以产生和输出CD4和CD8 T细胞。这些数据揭示了对TCR介导的存活信号的平行需求，但对TCR介导的成熟信号的不对称需求。
T cell receptor (TCR) signaling plays a central role in directing developmental fates of thymocytes. Current models suggest TCR signal duration directs CD4 vs CD8 lineage development. To investigate the role of TCR signaling during positive selection directly, we switched signaling off in a cohort of selecting thymocytes and followed, in time, their subsequent fate. We did this using an inducible Zap70 transgenic mouse model that allowed Zap70 dependent signaling to be turned on and then off again. Surprisingly, loss of TCR signaling in CD4+CD8lo thymocytes did not prevent their development to committed CD4 single positives (SP), nor their continued maturation to HSAloSPs. However, numbers of CD4SPs underwent a substantial decline following loss of Zap70 expression suggesting an essential survival role for the kinase. Termination of TCR signaling is considered an essential step in CD8 lineage development. Loss of Zap70 expression, however, resulted in the rapid death of CD8 lineage precursor thymocytes and a failure to generate CD8 SPs. Significantly, extending the window Zap70 expression was sufficient for generation and export of both CD4 and CD8 T cells. These data reveal a parallel requirement for TCR-mediated survival signaling, but an asymmetric requirement for TCR-mediated maturation signals.
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DOI：
10.1038/nri2416
发表时间：
2008-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
NEGISHI, I;MOTOYAMA, N;LOH, DY
通讯作者：
LOH, DY
DOI：
10.1073/pnas.96.18.10338
发表时间：
1999-08-31
影响因子：
11.1
作者：
Madsen, L;Labrecque, N;Fugger, L
通讯作者：
Fugger, L
影响因子：
15.3
作者：
Liu, XL;Adams, A;Wildt, KF;Aronow, B;Feigenbaum, L;Bosselut, R
通讯作者：
Bosselut, R
影响因子：
64.8
作者：
Carlson, Corey M.;Endrizzi, Bart T.;Jameson, Stephen C.
通讯作者：
Jameson, Stephen C.