Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China.
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
Cell Death Differ. 2022 Jul;29(7):1349-1363. doi: 10.1038/s41418-021-00921-w. Epub 2022 Jan 9.
Intestinal intraepithelial lymphocytes (IELs) are distributed along the length of the intestine and are considered the frontline of immune surveillance. The precise molecular mechanisms, especially epigenetic regulation, of their development and function are poorly understood. The trimethylation of histone 3 at lysine 27 (H3K27Me3) is a kind of histone modifications and associated with gene repression. Kdm6b is an epigenetic enzyme responsible for the demethylation of H3K27Me3 and thus promotes gene expression. Here we identified Kdm6b as an important intracellular regulator of small intestinal IELs. Mice genetically deficient for Kdm6b showed greatly reduced numbers of TCRαβCD8αα IELs. In the absence of Kdm6b, TCRαβCD8αα IELs exhibited increased apoptosis, disturbed maturation and a compromised capability to lyse target cells. Both IL-15 and Kdm6b-mediated demethylation of histone 3 at lysine 27 are responsible for the maturation of TCRαβCD8αα IELs through upregulating the expression of Gzmb and Fasl. In addition, Kdm6b also regulates the expression of the gut-homing molecule CCR9 by controlling H3K27Me3 level at its promoter. However, Kdm6b is dispensable for the reactivity of thymic precursors of TCRαβCD8αα IELs (IELPs) to IL-15 and TGF-β. In conclusion, we showed that Kdm6b plays critical roles in the maturation and cytotoxic function of small intestinal TCRαβCD8αα IELs.
肠道上皮内淋巴细胞（IELs）沿着肠道分布，被认为是免疫监视的第一线。它们的发育和功能的确切分子机制，特别是表观遗传调控，知之甚少。组蛋白 H3 赖氨酸 27 三甲基化（H3K27Me3）是一种组蛋白修饰，与基因抑制有关。Kdm6b 是一种表观遗传酶，负责 H3K27Me3 的去甲基化，从而促进基因表达。在这里，我们确定 Kdm6b 是小肠 IELs 的重要细胞内调节剂。Kdm6b 基因缺失的小鼠 TCRαβCD8αα IELs 数量显著减少。在没有 Kdm6b 的情况下，TCRαβCD8αα IELs 表现出增加的细胞凋亡、成熟紊乱和裂解靶细胞的能力受损。IL-15 和 Kdm6b 介导的组蛋白 H3 赖氨酸 27 的去甲基化都负责通过上调 Gzmb 和 Fasl 的表达来成熟 TCRαβCD8αα IELs。此外，Kdm6b 通过控制其启动子处的 H3K27Me3 水平，还调节肠道归巢分子 CCR9 的表达。然而，Kdm6b 对于 TCRαβCD8αα IELs（IELPs）对 IL-15 和 TGF-β 的反应性是可有可无的。总之，我们表明 Kdm6b 在小肠 TCRαβCD8αα IELs 的成熟和细胞毒性功能中发挥关键作用。
