Chd4 choreographs self-antigen expression for central immune tolerance.
Chd4 choreographs self-antigen expression for central immune tolerance.
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Chd4 精心设计自身抗原表达以实现中枢免疫耐受。
DOI：
10.1038/s41590-020-0717-2
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发表时间：
2020
影响因子：
30.5
通讯作者：
Takayanagi,Hiroshi
中科院分区：
文献类型：
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作者：
Tomofuji,Yoshihiko;Takaba,Hiroyuki;Suzuki,HiroshiI;Benlaribi,Rayene;Martinez,CristianDavidPeña;Abe,Yoshihiro;Morishita,Yasuyuki;Okamura,Tadashi;Taguchi,Akashi;Kodama,Tatsuhiko;Takayanagi,Hiroshi
胸腺髓质上皮细胞中混杂表达组织限制性自身抗原，从而消除胸腺中的自身反应性T细胞以防止自身免疫。这种表达依赖于转录因子Fezf2，以及转录调节因子Aire，但整个转录程序的画面一直模糊不清。在这里，我们发现染色质重塑者Chd4，也被称为Mi-2β，在髓质胸腺上皮细胞的自身抗原表达中起关键作用。为了最大限度地提高自身抗原表达的多样性，Fezf2和Aire利用了完全不同的转录机制，这两个机制都在Chd4的控制下。Chd4组织fezf2依赖基因的启动子区域，同时通过超增强子参与空气介导的自身抗原诱导。胸腺上皮细胞特异性缺失Chd4的小鼠表现出自身免疫表型，包括T细胞浸润。因此，Chd4在整合Fezf2和air介导的基因诱导建立中枢免疫耐受中起着关键作用。
Autoreactive T cells are eliminated in the thymus to prevent autoimmunity by promiscuous expression of tissue-restricted self-antigens in medullary thymic epithelial cells. This expression is dependent on the transcription factor Fezf2, as well as the transcriptional regulator Aire, but the entire picture of the transcriptional program has been obscure. Here, we found that the chromatin remodeler Chd4, also called Mi-2β, plays a key role in the self-antigen expression in medullary thymic epithelial cells. To maximize the diversity of self-antigen expression, Fezf2 and Aire utilized completely distinct transcriptional mechanisms, both of which were under the control of Chd4. Chd4 organized the promoter regions of Fezf2-dependent genes, while contributing to the Aire-mediated induction of self-antigens via super-enhancers. Mice deficient in Chd4 specifically in thymic epithelial cells exhibited autoimmune phenotypes, including T cell infiltration. Thus, Chd4 plays a critical role in integrating Fezf2- and Aire-mediated gene induction to establish central immune tolerance.