核小体重组和组蛋白去乙酰化酶（NuRD）复合物与BCL11B直接相互作用，调控小鼠T细胞发育。然而，NuRD复合物在成熟T细胞中的功能尚不清楚。在这里，我们研究了NuRD复合物或BCL11B关键亚基缺失的人类T细胞的命运和代谢。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，当MTA2、MBD2、CHD4或BCL11B被删除时，T细胞上调NK细胞相关受体和转录因子，溶解NK细胞靶标，并被重新编程为NK样细胞（ITNKs）。ITNKs上调OPA1表达，并表现出具有增强的氧化磷酸化（OXPHOS）活性的特征性延长线粒体。OPA1介导的增强OXPHOS提高了细胞乙酰辅酶A水平，从而通过调节特定靶点上的H3K27乙酰化，促进了ITNKs的重新编程效率和抗肿瘤效应。总之，我们的发现表明，NuRD复合物和BCL11B通过直接抑制NK细胞相关转录和通过代谢-表观遗传轴间接维持T细胞命运，提供了改善ITNKs的重新编程效率和抗肿瘤效应的策略。© 2023作者。

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.© 2023 The Authors.