Natural Killer Cell Recruitment and Differentiation

Innate lymphoid cells (ILCs) provide early immunity against pathogens and maintain tissue homeostasis. The best-studied ILCs are the natural killer (NK) cells that circulate in the blood, tissues, and lymph, and target virally infected and transformed cells to eliminate them. The type 1 innate lymphoid cells (ILC1s) do not circulate but reside near epithelial surfaces to protect against pathogens and maintain mucosal barrier integrity. In the uterine mucosa, we identified an abundant tissue-resident NK subset along with the less frequent ILC1s and cNK cells. We previously reported that the tissue-resident NK cells are specialized to the uterine mucosa and makeup 70% of the immune cells before and during pregnancy. Despite extensive research, fundamental gaps in our knowledge remain regarding the origin, differentiation, and function of tissue-resident NK cells in the uterine mucosa. Sex hormones such as progesterone induce the uterine mucosa to undergo cyclical tissue remodeling during the estrous cycle and critical uterine tissue transformation in pregnancy. In addition to progesterone’s role in reproduction, there is growing evidence of progesterone modulating immune cell function to affect the outcome of infections at mucosal sites. Indeed, we present preliminary data to support a pathway of progesterone-induced tissue-resident NK cell differentiation that is mediated through circulating cNK cells in the uterine mucosa. To test the hypothesis that circulating cNK cells encounter progesterone in the uterine mucosa, differentiate into tissue-resident NK cells, and are tolerant during pregnancy we propose the following Specific Aims: 1) Determine the signals that differentiate cNK cells-derived NK cells in the uterine mucosa. Elucidate if cNK-derived tissue-resident NK cells require direct progesterone signaling to drive normal pregnancy. 2) Investigate the function of cNK-derived tissue-resident NK cells in pregnancy. Determine if progesterone abrogates the cytotoxicity of cNK-derived tissue-resident NK cells thereby contributing to tolerance of the semi-allogeneic fetus. Thus, the goal of these studies is to better understand the tissue-resident NK cell origin, tissue-specific signals that govern their differentiation, and their function in the uterine mucosal tissue.