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.

胸腺中的自身反应性 T 细胞被消除，通过髓质胸腺上皮细胞中组织限制性自身抗原的混杂表达来预防自身免疫。这种表达依赖于转录因子 Fezf2 以及转录调节因子 Aire，但转录程序的整个过程一直是模糊的。在这里，我们发现染色质重塑因子 Chd4（也称为 Mi-2β）在胸腺髓质上皮细胞自身抗原表达中发挥关键作用。为了最大限度地提高自身抗原表达的多样性，Fezf2 和 Aire 利用完全不同的转录机制，这两种机制均受 Chd4 的控制。 Chd4 组织 Fezf2 依赖性基因的启动子区域，同时通过超级增强子促进艾尔介导的自身抗原的诱导。尤其是胸腺上皮细胞中缺乏 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 Aire 介导的基因诱导以建立中枢免疫耐受方面发挥着关键作用。