Zap70 is essential for long-term survival of naive CD8 T cells.
Zap70 is essential for long-term survival of naive CD8 T cells.
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ZAP70对于幼稚CD8 T细胞的长期存活至关重要。
DOI：
10.4049/jimmunol.1400858
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Seddon B
中科院分区：
文献类型：
--
作者：
Schim van der Loeff I;Hsu LY;Saini M;Weiss A;Seddon B
初始T细胞的存活需要T细胞受体（TCR）与自身肽 - 主要组织相容性抗原结合。传递这种存活信号所需的信号通路了解甚少。在此，我们探讨酪氨酸激酶Zap70是否为初始CD8 T细胞传递存活信号所必需。在缺乏Zap70表达的情况下，胸腺发育完全受阻。利用四环素诱导的Zap70转基因（TetZap70），Zap70缺陷的TCR转基因F5小鼠的胸腺发育得以恢复。给小鼠喂食多西环素（dox）以诱导Zap70表达，导致外周初始细胞群重新增殖。然后通过撤去多西环素消除Zap70转基因表达。Zap70缺陷的初始CD8 T细胞的存活取决于宿主环境。在T细胞区室完整的宿主中，在缺乏Zap70表达的情况下，初始T细胞迅速死亡。在淋巴细胞减少的宿主中，Zap70缺陷的T细胞以白细胞介素 - 7（IL - 7）依赖的方式存活时间长得多，但无法进行淋巴细胞减少诱导的增殖。对混合骨髓嵌合体的分析表明，完整的Zap70依赖性信号对于新迁出胸腺的细胞整合到成熟的初始细胞区室是重要的。最后，我们探讨了Zap70的酪氨酸315和319所赋予的衔接子功能对于稳态TCR信号的传递是否是必需的。这是通过分析表达突变型Zap70（其中这些残基已突变为丙氨酸，即Zap70YYAA）的F5小鼠来进行的。诱导性Zap70表达挽救了F5 TetZap70 Zap70YYAA小鼠的胸腺发育。然而，在缺乏野生型Zap70表达的情况下，Zap70YYAA突变体无法传递存活或增殖性稳态信号。
Survival of naive T cells requires engagement of T cell receptor (TCR) with self-peptide major histocompatibility antigens. The signalling pathways required to transmit this survival signal are poorly understood. Here, we ask whether the tyrosine kinase Zap70 is required to transmit survival signals in naive CD8 T cells. In the absence of Zap70 expression, thymic development is completely blocked. Using a tetracycline inducible Zap70 transgene (TetZap70), thymic development of Zap70-deficient TCR transgenic F5 mice was restored. Feeding mice doxycycline (dox) to induce Zap70 expression resulted in repopulation of the peripheral naive compartment. Zap70 transgene expression was then ablated by withdrawal of dox. Survival of Zap70-deficient naive CD8 T cells depended on host environment. In hosts with a replete T cell compartment, naive T cells died rapidly in the absence of Zap70 expression. In lymphopenic hosts, Zap70-deficient T cells survived far longer, in an IL-7 dependent manner, but failed to undergo lymphopenia-induced proliferation. Analysing mixed bone marrow chimeras revealed that intact Zap70 dependent signalling was important for integration of recent thymic emigrants into the mature naive compartment. Finally, we asked whether adaptor function conferred by Zap70 tyrosines 315 and 319 was necessary for transmission of homeostatic TCR signals. This was done by analysing F5 mice expressing mutant Zap70 in which these residues had been mutated to alanines (Zap70YYAA). Inducible Zap70 expression rescued thymic development in F5 TetZap70 Zap70YYAA mice. However, in the absence of WT Zap70 expression, Zap70YYAA mutant failed to transmit either survival or proliferative homeostatic signals.
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DOI：
10.1084/jem.20082902
发表时间：
2009-10-26
期刊：
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影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Butz, Eric A
影响因子：
4.4
作者：
Seddon, B;Zamoyska, R
通讯作者：
Zamoyska, R
影响因子：
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作者：
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通讯作者：
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DOI：
10.4049/jimmunol.1303085
发表时间：
2014-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Sinclair C;Seddon B
通讯作者：
Seddon B