The nucleosome remodeling and histone deacetylase (NuRD) complex physically associates with BCL11B to regulate murine T-cell development. However, the function of NuRD complex in mature T cells remains unclear. Here, we characterize the fate and metabolism of human T cells in which key subunits of the NuRD complex or BCL11B are ablated. BCL11B and the NuRD complex bind to each other and repress natural killer (NK)-cell fate in T cells. In addition, T cells upregulate the NK cell-associated receptors and transcription factors, lyse NK-cell targets, and are reprogrammed into NK-like cells (ITNKs) upon deletion of MTA2, MBD2, CHD4, or BCL11B. ITNKs increase OPA1 expression and exhibit characteristically elongated mitochondria with augmented oxidative phosphorylation (OXPHOS) activity. OPA1-mediated elevated OXPHOS enhances cellular acetyl-CoA levels, thereby promoting the reprogramming efficiency and antitumor effects of ITNKs via regulating H3K27 acetylation at specific targets. In conclusion, our findings demonstrate that the NuRD complex and BCL11B cooperatively maintain T-cell fate directly by repressing NK cell-associated transcription and indirectly through a metabolic-epigenetic axis, providing strategies to improve the reprogramming efficiency and antitumor effects of ITNKs.

中文翻译：

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BCL11B 和 NuRD 复合物协同守护 T 细胞命运并抑制 T 细胞中 OPA1 介导的线粒体融合

核小体重塑和组蛋白脱乙酰酶 (NuRD) 复合物与 BCL11B 物理结合，调节小鼠 T 细胞发育。然而，NuRD 复合物在成熟 T 细胞中的功能仍不清楚。在这里，我们描述了人类 T 细胞的命运和代谢，其中 NuRD 复合物或 BCL11B 的关键亚基被消除。BCL11B 和 NuRD 复合物相互结合并抑制 T 细胞中的自然杀伤 (NK) 细胞命运。此外，T 细胞上调 NK 细胞相关受体和转录因子，裂解 NK 细胞靶标，并在删除 MTA2、MBD2、CHD4 或 BCL11B 后重编程为 NK 样细胞 (ITNK)。ITNK 增加 OPA1 表达，并表现出特征性的细长线粒体，并增强氧化磷酸化 (OXPHOS) 活性。OPA1 介导的 OXPHOS 升高可增强细胞乙酰辅酶 A 水平，从而通过调节特定靶点的 H3K27 乙酰化来促进 ITNK 的重编程效率和抗肿瘤作用。总之，我们的研究结果表明，NuRD 复合物和 BCL11B 通过抑制 NK 细胞相关转录直接并通过代谢表观遗传轴间接协同维持 T 细胞命运，为提高 ITNK 的重编程效率和抗肿瘤作用提供了策略。