IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells.
IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vγ6(+)γδ T cells.
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DOI：
10.1038/ncomms8464
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发表时间：
2015-06-25
影响因子：
16.6
通讯作者：
Iwakura Y
中科院分区：
文献类型：
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作者：
Akitsu A;Ishigame H;Kakuta S;Chung SH;Ikeda S;Shimizu K;Kubo S;Liu Y;Umemura M;Matsuzaki G;Yoshikai Y;Saijo S;Iwakura Y
产生白细胞介素-17（IL-17）的γδ T（γδ17）细胞与炎症性疾病有关，但其潜在的致病机制尚不清楚。在这里，我们表明，CD 4+和γδ17细胞都需要在IL-1受体拮抗剂（IL-1 Ra）缺陷小鼠的自身免疫性关节炎的发展。具体而言，活化的CD 4 + T细胞通过诱导关节中的CCL 2表达来指导γδ T细胞浸润。此外，IL-17报告小鼠揭示了CCR 2 + γδ T细胞的Vγ6+亚群在发炎关节中优先产生IL-17。重要的是，由于IL-1 Ra通常抑制γδ T细胞上的IL-1 R表达，IL-1 Ra缺陷小鼠在Vγ6+细胞上表现出升高的IL-1 R表达，这在诱导它们产生IL-17中起关键作用。我们的研究结果表明，适应性免疫和先天性免疫以协调的方式诱导自身免疫性疾病的致病机制。 γδ T细胞活化的控制仍不完全清楚。在这里，作者表明，在自身免疫性关节炎的发展过程中，αβ CD 4 + T细胞将产生IL-17的γδ T细胞的一个亚群募集到关节中，并且这两种成分对于在该疾病的小鼠模型中引起病理学是必不可少的。
Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4+ and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4+ T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6+ subset of CCR2+ γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6+ cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner. Control of γδ T-cell activation remains incompletely understood. Here the authors show that during autoimmune arthritis development αβ CD4+ T cells recruit a subset of IL-17-producing γδ T cells to the joints, and that both components are essential to cause pathology in a mouse model of the disease.