GFI1-FOXO1 axis regulate NK cell maturation and function [RNA-seq]

Natural killer cells protect against malignant and virally-infected cells through a tightly regulated differentiation, maturation, and homeostatic program. The signals guiding differentiation of NK cells has not yet been fully elucidated. GFI1 is a transcriptional repressor broadly expressed in bone marrow progenitors and adaptive immune cells and acts to shape differentiation but has not been defined in NK cells. We show that GFI1 is differentially expressed across NK cell subsets but is not required for the development of immature (Imm) NK cell. Instead, GFI1 regulates the checkpoints that control the transition from Imm to mature NK stages (M1 and M2). Using multiomics approaches, we show that GFI1 regulates FOXO1 and EOMES signalling in mature NK cells and is critical for NK cell division and maturation. Furthermore, we show that the GFI1-FOXO1 axis is essential for protection against tumor metastasis through NK cell activation and effector functions, highlighting the important role of GFI1 in innate immune regulation.