The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4+ T cells
The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4+ T cells
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DOI：
10.1126/scisignal.aar3083
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发表时间：
2018-07-10
影响因子：
7.3
通讯作者：
Saoudi, Abdelhadi
中科院分区：
文献类型：
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作者：
Gaud, Guillaume;Roncagalli, Romain;Saoudi, Abdelhadi
T细胞的活化需要鸟嘌呤核苷酸交换因子VAV1。我们使用内源性VAV1分子上附着亲和纯化标签的小鼠，通过定量质谱分析了激活VAV1周围组装的信号复合物。共鉴定出50个VAV1结合伙伴，其中大多数先前未报道参与VAV1信号传导。其中包括CD226，一种免疫细胞的共刺激分子。CD226的参与诱导VAV1的酪氨酸磷酸化，并与T细胞受体（TCR）信号协同，特异性增强人CD4(+) T细胞产生白细胞介素-17 （IL-17）。此外，TCR和与自身免疫相关的CD226风险变体（rs763361）的共同作用进一步增强了VAV1的激活和IL-17的产生。因此，我们的研究揭示了在生理和病理T细胞反应中，TCR和CD226之间存在一种基于vav1的协同串扰，为靶向CD226治疗自身免疫性疾病提供了合理的依据。
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.