Deciphering the Origin and Function of Tissue-Resident Group 1 Innate Lymphoid Cells

Abstract

Group 1 innate lymphoid cells (ILCs) are pivotal for host defense against pathogens and tumors, encompassing circulating and resident cell populations. Among those, conventional Natural Killer (cNK) cells represent the circulating fraction, whereas the newly discovered tissue-resident group 1 ILCs comprise ILC1s and tissue-resident NK (trNK) cells. As local orchestrators of type 1 immunity, tissue-resident group 1 ILCs have a profound impact on health and disease, yet their precise origin and function are enigmatic. Using a combination of fate mapping, single-cell proteomics and transcriptomics, histology, as well as in vitro and in vivo functional assays, we comprehensively investigated the ontogeny, development, and function of tissue-resident group 1 ILCs. Our findings reveal that cNK cells are exclusively generated in the bone marrow (BM) and exhibit constant turnover throughout life, whereas ILC1s and trNK cells are seeded in waves during embryogenesis and early adolescence. A first wave of ILC1s emerges in the fetal liver and gives rise to hepatic ILC1s, which persist and self-maintain locally throughout adulthood, forming a highly cytotoxic subset. After birth, a second, BM-derived wave establishes new ILC1 populations in various tissues but also generates a lineage of trNK cells that acquires tissue residency in various glandular tissues. We identify autocrine transforming growth factor-β1 (TGF-β1) as a crucial driver for trNK cell development and maintenance, and demonstrate that, similar to hepatic ILC1s, trNK cells undergo a Hobit-dependent differentiation pathway leading to cytotoxicity. Moreover, our work shows that NK cell-derived TGF-β allows expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributes to its control in the salivary gland (SG). Finally, translating our findings into humans, we corroborate the vital function of NK cells in viral control and discover that human liver-resident NK cells might be the true counterpart of murine ILC1s. These findings elucidate key ontogenic features of group 1 ILCs, shedding light on tissue-specific networks driving differentiation and function, with implications for therapeutic interventions.