Medullary thymic epithelial cells (mTECs) play a central role in the establishment of T cell central immunological tolerance by promiscuously expressing tissue-restricted antigens (TRAs) and presenting them to developing T cells, leading to deletion of T cells responding to self-antigens. However, molecular mechanisms especially epigenetic regulation of mTEC homeostasis and TRA expression remain elusive. Here we show that the H3K27 demethylase Kdm6b is essential to maintain the postnatal thymic medulla by promoting mTEC survival and regulating the expression of TRA genes. Moreover, mice lacking Kdm6b developed pathological autoimmune disorders. Mechanically, Kdm6b exerted its function by reducing repressive H3K27 trimethylation (H3K27me3) at the promoters of anti-apoptotic gene Bcl2 and a set of Aire-dependent TRA genes. Thus, our findings reveal a dual role of Kdm6b in the regulation of mTEC-mediated T cell central tolerance.

中文翻译：

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组蛋白 H3 赖氨酸 27 脱甲基酶 Kdm6b 在髓质胸腺上皮细胞的稳态和功能中的关键作用。

髓质胸腺上皮细胞 (mTEC) 通过混杂表达组织限制性抗原 (TRA) 并将其呈递给发育中的 T 细胞，导致对自身抗原有反应的 T 细胞缺失，从而在 T 细胞中枢免疫耐受的建立中发挥核心作用。然而，分子机制，尤其是 mTEC 稳态和 TRA 表达的表观遗传调控仍然难以捉摸。在这里，我们表明 H3K27 去甲基化酶 Kdm6b 通过促进 mTEC 存活和调节 TRA 基因的表达，对于维持出生后胸腺髓质至关重要。此外，缺乏 Kdm6b 的小鼠会出现病理性自身免疫性疾病。在机械上，Kdm6b 通过减少抗凋亡基因 Bcl2 和一组 Aire 依赖性 TRA 基因启动子处的抑制性 H3K27 三甲基化 (H3K27me3) 来发挥其功能。因此，