Rbp-Jκ controls NK cell late maturation and migration via chromatin landscape remodeling

Abstract

Significance Despite the established role of Rbp-Jκ as the master transcriptional regulator of Notch signaling, its cell-intrinsic functions in natural killer (NK) cells remain unknown. In this study, we integrate genetic ablation (Ncr1iCre × Rbp-Jκfl/fl) studies with scRNA-seq, scATAC-seq, bulk ATAC-seq, CUT&Tag, and functional assays to elucidate the mechanisms underlying the regulatory role of Rbp-Jκ in NK cells. Our results demonstrate that Rbp-Jκ orchestrates NK cell chromatin remodeling to control maturation, effector function, and migration. Mechanistically, Kruppel-like factor 2 (Klf2) functions as a critical downstream transcriptional effector of Rbp-Jκ that orchestrates NK cell maturation and migration. These findings establish Rbp-Jκ as a central regulator that links developmental checkpoints to effector function, providing strategies for increasing NK cell generation and tumor infiltration.