ADAR1-mediated RNA editing is required for thymic self-tolerance and inhibition of autoimmunity
ADAR1-mediated RNA editing is required for thymic self-tolerance and inhibition of autoimmunity
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DOI：
10.15252/embr.201846303
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发表时间：
2018-12-01
期刊：
影响因子：
7.7
通讯作者：
Kawahara, Yukio
中科院分区：
文献类型：
--
作者：
Nakahama, Taisuke;Kato, Yuki;Kawahara, Yukio
T细胞在适应性免疫系统中起着至关重要的作用，它们的成熟过程受到严格的调控。作用于RNA 1的腺苷脱氨酶（ADAR 1）是负责dsRNA中腺苷至肌苷RNA编辑的酶，并且ADAR 1的缺失通过黑素瘤分化相关蛋白5（MDA 5）激活先天免疫感应应答，其将未编辑的dsRNA解释为非自身。虽然ADAR 1在胸腺中高度表达，但其在适应性免疫系统中的作用，特别是在T细胞中，仍然是难以捉摸的。在这里，我们证明了T细胞特异性Adar1缺失小鼠胸腺T细胞成熟异常，包括受损的负选择和自身免疫，如自发性结肠炎。这是由干扰素刺激的基因的过度表达引起的，这减少了T细胞受体（TCR）信号转导，这是由于ADAR 1缺陷胸腺细胞中RNA编辑的失败。有趣的是，同时缺失MDA5可以恢复胸腺细胞成熟并预防结肠炎。这些发现表明，通过ADAR 1介导的RNA编辑阻止内源性dsRNA的MDA 5传感是预防先天性免疫应答和T细胞介导的自身免疫所必需的。
T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine-to-inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation-associated protein 5 (MDA5), which interprets unedited dsRNA as non-self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive. Here, we demonstrate that T cell-specific deletion of Adar1 in mice causes abnormal thymic T cell maturation including impaired negative selection and autoimmunity such as spontaneous colitis. This is caused by excessive expression of interferon-stimulated genes, which reduces T cell receptor (TCR) signal transduction, due to a failure of RNA editing in ADAR1-deficient thymocytes. Intriguingly, concurrent deletion of MDA5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA5 sensing of endogenous dsRNA by ADAR1-mediated RNA editing is required for preventing both innate immune responses and T cell-mediated autoimmunity.