NFAT1 Regulates Systemic Autoimmunity through the Modulation of a Dendritic Cell Property
NFAT1 Regulates Systemic Autoimmunity through the Modulation of a Dendritic Cell Property
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DOI：
10.4049/jimmunol.1700882
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发表时间：
2017-11-01
影响因子：
4.4
通讯作者：
Im, Sin-Hyeog
中科院分区：
文献类型：
--
作者：
Chae, Chang-Suk;Kim, Gi-Cheon;Im, Sin-Hyeog
转录因子NFAT 1在T淋巴细胞的稳态中起关键作用。然而，其在非CD 4（+）T细胞中的功能重要性，特别是在系统性免疫疾病中，在很大程度上是未知的。在这项研究中，我们报告，NFAT 1调节树突状细胞（DC）的耐受性，并抑制系统性自身免疫性重症肌无力（EAMG）作为一个模型。重症肌无力和EAMG是T细胞依赖性、Ab介导的自身免疫性疾病，其中乙酰胆碱受体是主要的自身抗原。NFAT 1基因敲除小鼠对EAMG的易感性更高，Th 1/Th 17细胞应答增强。NFAT 1缺陷导致DC的表型改变，其显示NF-κ B介导的信号传导途径的过度活化和NF-κ B（p50）与IL-6和IL-12的启动子的结合增强。因此，NFAT 1敲除的DC产生更高水平的促炎细胞因子，如IL-1 β、IL-6、IL-12和TNF-α，其优先诱导Th 1/Th 17细胞分化。我们的数据表明，NFAT 1可能限制了DC中NF-κ B介导的促炎反应的过度激活，并通过作为DC耐受的关键调节因子来抑制自身免疫。
The transcription factor NFAT1 plays a pivotal role in the homeostasis of T lymphocytes. However, its functional importance in non-CD4(+) T cells, especially in systemic immune disorders, is largely unknown. In this study, we report that NFAT1 regulates dendritic cell (DC) tolerance and suppresses systemic autoimmunity using the experimental autoimmune myasthenia gravis (EAMG) as a model. Myasthenia gravis and EAMG are T cell-dependent, Ab-mediated autoimmune disorders in which the acetylcholine receptor is the major autoantigen. NFAT1-knockout mice showed higher susceptibility to EAMG development with enhanced Th1/Th17 cell responses. NFAT1 deficiency led to a phenotypic alteration of DCs that show hyperactivation of NF-kappa B-mediated signaling pathways and enhanced binding of NF-kappa B (p50) to the promoters of IL-6 and IL-12. As a result, NFAT1-knockout DCs produced much higher levels of proinflammatory cytokines such as IL-1 beta, IL-6, IL-12, and TNF-alpha, which preferentially induce Th1/Th17 cell differentiation. Our data suggest that NFAT1 may limit the hyperactivation of the NF-kappa B-mediated proinflammatory response in DCs and suppress autoimmunity by serving as a key regulator of DC tolerance.