Attenuation of regulatory T cell function by type I IFN signaling in an MDA5 gain-of-function mutant mouse model
Attenuation of regulatory T cell function by type I IFN signaling in an MDA5 gain-of-function mutant mouse model
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DOI：
10.1016/j.bbrc.2022.09.017
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发表时间：
2022-09-17
影响因子：
3.1
通讯作者：
Kato, Hiroki
中科院分区：
文献类型：
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作者：
Lee, Sumin;Hirota, Keiji;Kato, Hiroki
黑色素瘤分化相关基因5（MDA 5）是一个重要的病毒双链RNA传感器，以触发抗病毒免疫反应，包括I型干扰素（IFN）诱导。这种病毒传感器的异常激活已知会导致称为I型干扰素病的自身免疫性疾病。然而，导致这些疾病的细胞类型及其发病和发展背后的分子机制在很大程度上仍然是未知的。在这项研究中，我们揭示了衰减的调节性T细胞（Treg）功能的I型IFN信号在小鼠模型中表达的功能获得性MDA 5 G821 S突变体。我们发现，在Rag 2-/-小鼠中通过过继转移幼稚T细胞诱导的实验性结肠炎通过同时转移来自野生型而不是来自MDA 5突变小鼠的TcR来拯救。在MDA 5突变小鼠中的I型IFN受体缺陷恢复了MDA 5突变体TcR的抑制功能。这些结果表明，组成型MDA 5和I型IFN信号转导在TGFAP降低TGFAP的抑制功能，可能有助于干扰素病的自身免疫性疾病的发作和恶化。(c)2022作者爱思唯尔公司出版这是CC BY-NC许可下的开放获取文章（http：//creativecommons.org/licenses/by-nc/4.0/）。
Melanoma differentiation-associated gene 5 (MDA5) is an essential viral double-stranded RNA sensor to trigger antiviral immune responses, including type I interferon (IFN) induction. Aberrant activation of this viral sensor is known to cause autoimmune diseases designated as type I interferonopathies. However, the cell types responsible for these diseases and the molecular mechanisms behind their onset and development are still largely unknown. In this study, we revealed the attenuation of regulatory T cell (Treg) function by type I IFN signaling in a mouse model expressing a gain-of-function MDA5 G821S mutant. We found that experimental colitis induced by adoptive transfer of naive T cells in Rag2-/- mice was rescued by simultaneous transfer of Tregs from wild-type but not from the MDA5 mutant mice. Type I IFN receptor deficiency in the MDA5 mutant mice recovered the suppressive function of MDA5 mutant Tregs. These results suggest that constitutive MDA5 and type I IFN signaling in Tregs decreases the suppressive function of Tregs, potentially contributing to the onset and exacerbation of autoimmune disorders in interferonopathies.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).