Kumar Ashok, Humphreys Troy D, Kremer Kimberly N, Bramati Patricia S, Bradfield Lavone, Edgar Contessa E, Hedin Karen E
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Immunity. 2006 Aug;25(2):213-24. doi: 10.1016/j.immuni.2006.06.015.
SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.
基质细胞衍生因子-1α（SDF-1α，即CXCL12）通过其受体CXCR4发出信号，刺激T细胞趋化性和基因表达。ζ链相关蛋白激酶70（ZAP-70）酪氨酸激酶在T细胞中关键性地介导了依赖SDF-1α的迁移以及细胞外信号调节激酶（ERK）丝裂原活化蛋白（MAP）激酶的持续激活。然而，CXCR4或其他G蛋白偶联受体激活ZAP-70的分子机制尚未明确。在此我们表明，SDF-1α刺激CXCR4与T细胞受体（TCR）发生物理性结合，并利用TCR的ZAP-70结合免疫受体酪氨酸活化基序（ITAM）结构域进行信号转导。该信号通路介导了SDF-1α对T细胞的多种效应，包括ERK MAP激酶活性的持续增强、细胞内钙离子浓度升高、强劲的活化蛋白-1（AP-1）转录活性以及SDF-1α对细胞因子分泌的共刺激作用。这些结果为理解SDF-1α及其他趋化因子对免疫的作用提示了新的模式。
