Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
EMBO Rep. 2018 Dec;19(12). doi: 10.15252/embr.201846303. Epub 2018 Oct 25.
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 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.
T 细胞在适应性免疫系统中发挥着关键作用，其成熟过程受到严格调控。腺苷脱氨酶作用于 RNA1（ADAR1）是负责双链 RNA 中腺苷向肌苷 RNA 编辑的酶，ADAR1 的缺失通过黑色素瘤分化相关蛋白 5（MDA5）激活先天免疫感应反应，MDA5 将未经编辑的双链 RNA 解释为非自身。尽管 ADAR1 在胸腺中高度表达，但它在适应性免疫系统中的作用，特别是在 T 细胞中，仍然难以捉摸。在这里，我们证明了在小鼠中特异性敲除 会导致胸腺 T 细胞成熟异常，包括负选择受损和自身免疫，如自发性结肠炎。这是由于干扰素刺激基因的过度表达，由于 ADAR1 缺陷的胸腺细胞中的 RNA 编辑失败，导致 T 细胞受体 (TCR) 信号转导减少。有趣的是，同时敲除 MDA5 可恢复胸腺细胞成熟并预防结肠炎。这些发现表明，ADAR1 介导的 RNA 编辑防止 MDA5 感应内源性双链 RNA 对于预防先天免疫反应和 T 细胞介导的自身免疫都是必需的。
