Bécart Stéphane, Charvet Céline, Canonigo Balancio Ann J, De Trez Carl, Tanaka Yoshihiko, Duan Wei, Ware Carl, Croft Michael, Altman Amnon
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
J Clin Invest. 2007 Aug;117(8):2164-75. doi: 10.1172/JCI31640.
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 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 Ca(2+) 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.
T细胞的SWAP-70样衔接蛋白（SLAT）是一种新型的Rho GTP酶鸟嘌呤核苷酸交换因子，在Th2细胞中上调，但其生理功能尚不清楚。我们发现，SLAT基因敲除（SLAT-/-）小鼠在胸腺细胞分化的最早阶段之一，即双阴性1（DN1）阶段出现发育缺陷，导致外周T细胞数量减少。SLAT-/-外周CD4+ T细胞表现出TCR/CD28诱导的增殖和IL-2产生受损，添加外源性IL-2可挽救这种情况。重要的是，SLAT-/-小鼠不仅在引发Th2介导的肺部炎症反应方面严重受损，在引发Th1介导的肺部炎症反应方面也严重受损，分别表现为气道嗜中性粒细胞增多和嗜酸性粒细胞增多减少。肺中Th1和Th2细胞因子的水平也明显降低，与肺部炎症的减轻平行。这种在Th1/Th2反应方面的缺陷在体外也很明显，其原因是内质网钙库的钙动员严重减少，从而导致TCR/CD28诱导的活化T细胞核因子1/2（NFATc1/2）转位缺陷。因此，SLAT是胸腺DN1细胞扩增、T细胞活化以及Th1和Th2炎症反应所必需的。
