Ye Jian, Shi Hao, Shen Ye, Peng Chao, Liu Yan, Li Chenyu, Deng Kejing, Geng Jianguo, Xu Tian, Zhuang Yuan, Zheng Biao, Tao Wufan
State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, National Center for International Research of Development and Disease, School of Life Sciences, Fudan University, Shanghai 200433, China;
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109;
J Immunol. 2015 Feb 15;194(4):1654-64. doi: 10.4049/jimmunol.1401692. Epub 2015 Jan 21.
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.
T细胞的发育和稳态均受TCR信号调控。分别由蛋白激酶和磷酸酶催化的蛋白磷酸化和去磷酸化，是控制TCR识别抗原触发的多个下游通路的重要开关。蛋白酪氨酸磷酸酶参与近端TCR信号的负调控，这一点已有充分的文献记载。然而，TCR信号在远端TCR信号通路中是如何终止或减弱的，在很大程度上尚不清楚。我们研究了丝氨酸/苏氨酸蛋白磷酸酶（PP）6在TCR信号传导中的功能。小鼠中PP6的T细胞谱系特异性缺失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Vγ6Vδ1(+) T细胞的优先扩增。PP6缺陷的外周CD4(+)辅助细胞和CD8(+)溶细胞细胞均无法维持幼稚状态，而成为快速增殖且寿命短暂的效应细胞。PP6缺陷导致多个远端TCR信号分子，包括丝裂原活化蛋白激酶（MAPK）、蛋白激酶B（AKT）和核因子κB（NF-κB）的深度过度激活。我们的研究表明，PP6作为一种关键的负调控因子，不仅控制αβ和γδ谱系的发育，还通过防止幼稚T细胞在抗原刺激前过早激活来维持其稳态。
