Autocrine TGF-1 drives tissue-specific differentiation and function of resident NK cells

Group 1 innate lymphoid cells (ILCs) encompass NK cells and ILC1s which have non-redundant roles in host protection against pathogens and cancer. Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-b (TGF-b) as a cell-autonomous driver for NK cell tissue-residency across multiple glandular tissues during development. Cell-intrinsic production of TGF- was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF- was redundant in tumors, our study revealed that NK cell-derived TGF- allowed expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-1, which is relevant for anti-viral immunity. Salivary glands were dissociated and CD45+ cells sorted before scRNA-seq using 10x Genomics platform.