PP6 Controls T Cell Development and Homeostasis by Negatively Regulating Distal TCR Signaling
PP6 Controls T Cell Development and Homeostasis by Negatively Regulating Distal TCR Signaling
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DOI：
10.4049/jimmunol.1401692
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Jian Ye;Hao Shi;Ye Shen;Chao Peng;Yan Liu;Chenyu Li;K. Deng;J. Geng;Tian Xu;Zhuang Yuan-Z
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文献类型：
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作者：
Jian Ye;Hao Shi;Ye Shen;Chao Peng;Yan Liu;Chenyu Li;K. Deng;J. Geng;Tian Xu;Zhuang Yuan-Z
T细胞的发育和稳态都受TCR信号的调节。分别由蛋白激酶和磷酸酶催化的蛋白磷酸化和去磷酸化充当控制由TCR识别Ag触发的多个下游途径的重要开关。已经充分证明蛋白酪氨酸磷酸酶参与近端TCR信号传导的负调控。然而，TCR信号如何在远端TCR信号传导途径中终止或减弱在很大程度上是未知的。我们研究了Ser/Thr蛋白磷酸酶（PP）6在TCR信号转导中的作用。小鼠中T细胞谱系特异性消除PP6导致胸腺阳性和阴性选择增强，以及胎儿来源的产生IL-17的V γ 6V δ 1 + T细胞的优先扩增。PP6缺陷的外周血CD4+辅助细胞和CD8+细胞溶解细胞都不能维持幼稚状态，成为快速增殖和短寿命的效应细胞。PP6缺陷导致多个远端TCR信号分子，包括MAPK、AKT和NF-κ B的高度活化。我们的研究表明，PP6作为一个关键的负调节因子，不仅控制α β和γ δ谱系的发展，而且还通过防止它们在Ag刺激前的过早激活来维持幼稚T细胞的稳态。
T cell development and homeostasis are both regulated by TCR signals. Protein phosphorylation and dephosphorylation, which are catalyzed by protein kinases and phosphatases, respectively, serve as important switches controlling multiple downstream pathways triggered by TCR recognition of Ags. It has been well documented that protein tyrosine phosphatases are involved in negative regulation of proximal TCR signaling. However, how TCR signals are terminated or attenuated in the distal TCR signaling pathways is largely unknown. We investigated the function of Ser/Thr protein phosphatase (PP) 6 in TCR signaling. T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection, and preferential expansion of fetal-derived, IL-17–producing Vγ6Vδ1+ T cells. Both PP6-deficient peripheral CD4+ helper and CD8+ cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells. PP6 deficiency led to profound hyperactivation of multiple distal TCR signaling molecules, including MAPKs, AKT, and NF-κB. Our studies demonstrate that PP6 acts as a critical negative regulator, not only controlling both αβ and γδ lineage development, but also maintaining naive T cell homeostasis by preventing their premature activation before Ag stimulation.