Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site.
Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site.
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DOI：
10.1016/j.immuni.2015.07.014
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发表时间：
2015-08-18
期刊：
影响因子：
32.4
通讯作者：
Caspi RR
中科院分区：
文献类型：
--
作者：
Horai R;Zárate-Bladés CR;Dillenburg-Pilla P;Chen J;Kielczewski JL;Silver PB;Jittayasothorn Y;Chan CC;Yamane H;Honda K;Caspi RR
已经获得突破血视网膜屏障的能力的活化的视网膜特异性T细胞被认为与自身免疫性葡萄膜炎（人类失明的主要原因）有因果关系。目前还不清楚这些自身反应性T细胞首先在哪里被激活，因为它们的同源抗原被隔离在免疫特权眼内。我们在一种新的自发性葡萄膜炎小鼠模型中证明，视网膜特异性T细胞的激活依赖于肠道微生物群。视网膜特异性T细胞活化涉及通过自身反应性T细胞受体（TCR）响应肠中的非同源抗原的信号传导，并且独立于内源性视网膜自身抗原。我们的研究结果不仅对人类葡萄膜炎的病因学有影响，而且还提出了这样一种可能性，即由眼内微生物激活的自身反应性TCR可能是比目前认识到的更常见的自身免疫性疾病的触发因素。
Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine, and was independent of the endogenous retinal autoantigen. Our findings not only have implications for etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes may be a more common trigger of autoimmune diseases than is currently appreciated.