Context-dependent role of type 3 innate lymphoid cells in mucosal protection

How group 3 innate lymphoid cells (ILC3) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, Th17 cells, and secondary lymphoid organs. ILC3 were dispensable for generation of Th17 and Th22 cell responses to commensal and pathogenic bacteria, and absence of ILC3 did not affect IL-22-production by CD4 T cells before or during infection. However, despite presence of IL-22-producing T cells, ILC3 and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell-sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with low dose Citrobacter rodentium. However, ILC3 increased pathogen tolerance at early timepoints of infection by activating tissue-protective immune pathways. Consequently, ILC3 were indispensable for survival of high dose infection. Our results demonstrate a crucial context-dependent role for ILC3 in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and Th17 cell functions.