BCL11B and the NuRD complex cooperatively guard T‐cell fate and inhibit OPA1‐mediated mitochondrial fusion in T cells.

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. Synopsis: While BCL11b is known to bind the NuRD complex and be required for T cell development, the function of these factors in mature T cells has so far been unclear. This work demonstrates how the NuRD complex and BCL11B together maintain T‐cells from reprogramming into NK cells. T cells are reprogrammed into NK‐like cells upon deletion of MTA2, MBD2, or CHD4.BCL11B associates with the NuRD complex to repress OPA1 expression in T cells.OPA1‐mediated mitochondrial fusion facilitates ITNK reprogramming and cytotoxicity by increasing OXPHOS.Acetyl‐CoA elevated by OXPHOS promotes NK‐cell‐associated genes expression and antitumor effects in ITNKs by regulating H3K27 acetylation. [ABSTRACT FROM AUTHOR]