Genetic variation underlying innate lymphoid cell phenotypes across hosts

Project Summary Maintenance of gut epithelial homeostasis requires signals from a specialized set of RORγt+ innate lymphoid cells (ILCs) that reside in mucosa. RORγt+ ILCs directly regulate the gut barrier by secreting cytokines that activate epithelial host defense mechanisms and reinforce gut barrier integrity. Among the RORγt+ ILCs, there exists a set of phenotypically diverse cells characterized by distinct patterns of cytokine secretion, transcription factor expression, and physical distribution. Although a comprehensive understanding of the diversity of RORγt+ ILCs is required to mechanistically determine how to manipulate these cells, the full spectrum of ILCs remains to be examined. Our objective is to characterize the diversity of ILC subtypes, and define their development, function, and spatial regulation. Our long-term goal is to exploit mechanisms that control distinct innate lymphocyte subtypes to selectively manipulate these cells in vivo and restore mucosal homeostasis after intestinal dysregulation. We identified a specialized population of RORγt+T-bet+ ILCs that exhibited distinct patterns of expression of the chemokine receptor CCR6 compared to related ILCs. We also found that this chemokine receptor expression is associated with enhanced secretion of epithelial cell-active cytokines and was strongly regulated by genetic variation. We hypothesize that genetic variation in mouse strains results in distinct patterns of spatially distributed ILCs in tissue, which alter the capacity of RORγt+ ILCs to secrete mucosal cytokines. In Aim 1, we will investigate the developmental pathway of these newly described ILCs and identify genetic mechanisms regulating their expression of CCR6. In Aim 2, we will determine the impact of CCR6 on tissue localization of natural ILCs and their contribution to barrier immunity. These studies will provide insight into how diverse configurations of innate immune cells caused by genetic variation can shape underlying mucosal fitness.