Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, CNRS, Inserm, Toulouse 31300, France.
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, Inserm, CNRS, 13288 Marseille, France.
Sci Signal. 2018 Jul 10;11(538):eaar3083. doi: 10.1126/scisignal.aar3083.
The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of interleukin-17 (IL-17) by primary human CD4 T cells. Moreover, co-engagement of the TCR and a risk variant of CD226 that is associated with autoimmunity (rs763361) further enhanced VAV1 activation and IL-17 production. Thus, our study reveals that a VAV1-based, synergistic cross-talk exists between the TCR and CD226 during both physiological and pathological T cell responses and provides a rational basis for targeting CD226 for the management of autoimmune diseases.
T 细胞的激活需要鸟嘌呤核苷酸交换因子 VAV1。我们使用一种在小鼠内源性 VAV1 分子上附着亲和纯化标签的方法，通过定量质谱分析了围绕激活的 VAV1 组装的信号复合物。鉴定出了 50 个 VAV1 结合伙伴，其中大多数以前没有报道过参与 VAV1 信号。其中包括免疫细胞的共刺激分子 CD226。CD226 的结合诱导 VAV1 的酪氨酸磷酸化，并与 T 细胞受体 (TCR) 信号协同作用，特异性增强原代人 CD4 T 细胞中白细胞介素-17 (IL-17) 的产生。此外，TCR 与与自身免疫相关的 CD226 的风险变体（rs763361）的共同结合进一步增强了 VAV1 的激活和 IL-17 的产生。因此，我们的研究表明，在生理和病理 T 细胞反应中，TCR 和 CD226 之间存在基于 VAV1 的协同串扰，并为靶向 CD226 以管理自身免疫性疾病提供了合理的依据。
