IQGAP1 restrains T‐cell cosignaling mediated by OX40
IQGAP1 restrains T‐cell cosignaling mediated by OX40
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IQGAP1 抑制 OX40 介导的 T 细胞共信号传导
DOI：
10.1096/fj.201900879rr
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
So Takanori
中科院分区：
文献类型：
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作者：
Okuyama Yuko;Nagashima Hiroyuki;Ushio‐Fukai Masuko;Croft Michael;Ishii Naoto;So Takanori
来自肿瘤坏死因子受体 (TNFR) 家族分子 OX40 (CD134) 的共刺激信号由活化的 T 细胞诱导，对于 T 细胞免疫非常重要。异常的 OX40 协同信号传导与自身免疫和炎症性疾病有关。然而，OX40 协同信号传导调节 T 细胞反应的分子机制仍不清楚。我们发现 OX40 在与其配体 OX40L 连接后与支架蛋白、含有 IQ 基序的 GTP 酶激活蛋白 1 (IQGAP1) 相关。来自 Iqgap1−/− 小鼠的初始 CD4+T 细胞在接受 OX40 联合信号传导后显示出增殖和细胞因子分泌增强。 C 末端 IQGAP1 区域负责与 OX40 的关联，TNFR 相关因子 2 (TRAF2) 连接这两种蛋白质。 Iqgap1−/−T 细胞中增强的细胞因子反应通过 C 末端 IQGAP1 的表达得以恢复。因此，IQGAP1 结合限制了 OX40 协同信号传导。与野生型小鼠相比，Iqgap1−/−小鼠实验性自身免疫性脑脊髓炎（EAE）的疾病严重程度显着加剧。此外，具有 Iqgap1−/−供体 CD4+T 细胞的受体小鼠表现出比野生型小鼠显着更高的 EAE 评分，并且 OX40 阻断导致 EAE 严重程度显着降低。因此，我们的研究定义了 OX40 协同信号传导的一个重要组成部分，它限制了抗原激活 T 细胞驱动的炎症。
A costimulatory signal from the tumor necrosis factor receptor (TNFR) family molecule OX40 (CD134), which is induced on activated T cells, is important for T‐cell immunity. Aberrant OX40 cosignaling has been implicated in autoimmune and inflammatory disorders. However, the molecular mechanism by which the OX40 cosignaling regulates the T‐cell response remains obscure. We found that OX40 associated with a scaffold protein, IQ motif‐containing GTPase‐activating protein 1 (IQGAP1) after ligation by its ligand OX40L. Naïve CD4+T cells fromIqgap1−/−mice displayed enhanced proliferation and cytokine secretion upon receiving OX40 cosignaling. A C‐terminal IQGAP1 region was responsible for its association with OX40, and TNFR‐associated factor 2 (TRAF2) bridged these two proteins. The enhanced cytokine response inIqgap1−/−T cells was restored by the expression of the C‐terminal IQGAP1. Thus, the IQGAP1 binding limits the OX40 cosignaling. Disease severity of experimental autoimmune encephalomyelitis (EAE) was significantly exacerbated inIqgap1−/−mice as compared to wild‐type mice. Additionally, recipient mice withIqgap1−/−donor CD4+T cells exhibited significantly higher EAE scores than those with their wild‐type counterparts, and OX40 blockade led to a significant reduction in the EAE severity. Thus, our study defines an important component of the OX40 cosignaling that restricts inflammation driven by antigen‐activated T cells.