SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling
SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling
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DOI：
10.1172/jci31640
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Altman, Amnon
中科院分区：
文献类型：
--
作者：
Becart, Stephane;Charvet, Celine;Altman, Amnon
SWAP-70样T细胞衔接子（SLAT）是一种新型Rho GTPases的鸟苷酸交换因子，在Th 2细胞中上调，但其生理功能尚不清楚。我们发现，SLAT（-/-）小鼠在胸腺细胞分化的最早阶段之一，双阴性1（DN 1）阶段表现出发育缺陷，导致外周T细胞数量减少。SLAT（-/-）外周CD 4（+）T细胞表现出ip TCR/CD 28诱导的增殖和IL-2产生受损，这通过添加外源性IL-2来挽救。重要的是，SLAT-/-小鼠不仅产生Th 2，而且产生Th 1介导的肺部炎症反应的能力严重受损，分别由气道嗜酸性粒细胞增多症和嗜酸性粒细胞增多症减少证明。肺中Th 1和Th 2细胞因子的水平也显著降低，与肺部炎症的减少平行。这种在体外也很明显的Th 1/Th 2应答的缺陷可追溯到ER储存中Ca 2+动员的严重减少，从而导致TCR/CD 28诱导的活化T细胞核因子1/2（NFATc 1/2）易位缺陷。因此，SLAT是胸腺DN 1细胞扩增、T细胞活化以及Th 1和Th 2炎症反应所必需的。
SWAP-70-like adapter of T cells (SLAT) is a novel guanine nucleotide exchange factor for Rho GTPases that is upregulated in Th2 cells, but whose physiological function is unclear. We show that SLAT(-/-) mice displayed a developmental defect at one of the earliest stages of thymocyte differentiation, the double-negative 1 (DN1) stage, leading to decreased peripheral T cell numbers. SLAT(-/-) peripheral CD4(+) T cells demonstrated impaired ip TCR/CD28-induced proliferation and IL-2 production, which was rescued by the addition of exogenous IL-2. Importantly, SLAT-/- mice were grossly impaired in their ability to mount not only Th2, but also Th1-mediated lung inflammatory responses, as evidenced by reduced airway neutrophilia and eosinophilia, respectively. Levels of Th1 and Th2 cytokine in the lungs were also markedly reduced, paralleling the reduction in pulmonary inflammation. This defect in mounting Th1/Th2 responses, which was also evident in vitro, was traced to a severe reduction in Ca2+ mobilization from ER stores, which consequently led to defective TCR/CD28-induced translocation of nuclear factor of activated T cells 1/2 (NFATc1/2). Thus, SLAT is required for thymic DN1 cell expansion, T cell activation, and Th1 and Th2 inflammatory responses.