Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis
Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis
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DOI：
10.1073/pnas.1010249107
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发表时间：
2010-10-26
影响因子：
11.1
通讯作者：
Zheng, Yi
中科院分区：
文献类型：
--
作者：
Guo, Fukun;Hildeman, David;Zheng, Yi
T细胞动态平衡对于免疫系统的正常运作是必不可少的。IL-7受体(IL-7R)和T细胞受体(TCR)信号在T细胞内稳态调节中起着关键作用。调节T细胞稳态的详细机制以及IL-7R和TCR信号是如何协调的在很大程度上是未知的。在这里，我们证明了T细胞特异性的细胞分裂周期42(CDC42)GTP酶的缺失导致成熟T细胞的严重丧失。CDC42基因缺失导致生长因子独立性-1(GFI-1)表达显著增加，并抑制IL-7Rα的表达。在没有CDC42的情况下，ERK1/2MAPK活性异常导致TCR介导的T细胞增殖增强。体内重组的CDC42突变体和效应器p21蛋白激活的蛋白激活蛋白1(PAK1)在CDC42缺陷的T细胞中的重组表明，PAK1是CDC42调节的T细胞动态平衡的必要条件和充分条件。因此，T细胞的动态平衡是通过CDC42-PAK1信号轴协同调节GFI-1-IL-7R控制的细胞因子反应和ERK介导的TCR信号强度来维持的。
T-cell homeostasis is essential for normal functioning of the immune system. IL-7 receptor (IL-7R) and T-cell receptor (TCR) signaling are pivotal for T-cell homeostatic regulation. The detailed mechanisms regulating T-cell homeostasis and how IL-7R and TCR signaling are coordinated are largely unknown. Here we demonstrate that T cell-specific deletion of cell-division cycle 42 (Cdc42) GTPase causes a profound loss of mature T cells. Deletion of Cdc42 leads to a markedly increased expression of growth factor independence-1 (Gfi-1) and represses expression of IL-7R alpha. In the absence of Cdc42, aberrant ERK1/2 MAP kinase activity results in enhanced, TCR-mediated T-cell proliferation. In vivo reconstitution of effector-binding-defective Cdc42 mutants and the effector p21 protein-activated kinase 1 (PAK1) into Cdc42-deficient T cells showed that PAK1 is both necessary and sufficient for Cdc42-regulated T-cell homeostasis. Thus, T-cell homeostasis is maintained through a concerted regulation of Gfi-1-IL-7R-controlled cytokine responsiveness and ERK-mediated TCR signaling strength by the Cdc42-PAK1 signaling axis.