Bécart Stéphane, Balancio Ann J Canonigo, Charvet Céline, Feau Sonia, Sedwick Caitlin E, Altman Amnon
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Immunity. 2008 Nov 14;29(5):704-19. doi: 10.1016/j.immuni.2008.08.015. Epub 2008 Oct 30.
SWAP-70-like adaptor of T cells (SLAT) is a guanine nucleotide exchange factor for Rho GTPases that regulates the development of T helper 1 (Th1) and Th2 cell inflammatory responses by controlling the Ca(2+)-NFAT signaling pathway. However, the mechanism used by SLAT to regulate these events is unknown. Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway. Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. Therefore, tyrosine-phosphorylation-mediated relocalization of SLAT to the site of antigen recognition is required for SLAT to exert its pivotal role in NFAT-dependent CD4(+) T cell differentiation.
T细胞的SWAP-70样衔接蛋白（SLAT）是一种Rho GTP酶的鸟嘌呤核苷酸交换因子，它通过控制Ca(2+)-NFAT信号通路来调节辅助性T细胞1（Th1）和Th2细胞炎症反应的发展。然而，SLAT调节这些事件的机制尚不清楚。在此，我们报告T细胞受体（TCR）诱导的SLAT向免疫突触的转位需要Lck介导的位于免疫受体酪氨酸基激活基序样序列中的两个酪氨酸残基的磷酸化，但与SLAT的PH结构域无关。这种亚细胞重新定位与NFAT途径的激活相关联且是其激活所必需的。此外，SLAT的Dbl同源（催化）结构域的膜靶向足以以Cdc42依赖性方式触发TCR介导的NFAT激活以及Th1和Th2分化。因此，SLAT酪氨酸磷酸化介导的重新定位到抗原识别位点是SLAT在依赖NFAT的CD4(+) T细胞分化中发挥关键作用所必需的。
