IL-21 Controls ILC3 Cytokine Production and Promotes a Protective Phenotype in a Mouse Model of Colitis

Group 3 innate lymphoid cells (ILC3s) have dual roles in intestinal health, acting in both protective and pathogenic capacities, and importantly, modulations in this population of innate lymphoid cells have been implicated in inflammatory bowel disease. Further, subpopulations of ILC3s have been described as serving specific functions in maintaining homeostasis or responding to infection, and aberrant activation of one or more of these subpopulations could exacerbate inflammatory bowel disease. However, the signals that enforce the protective and pathogenic features of ILC3s are not fully elucidated. In this article, we show that IL-21, a cytokine primarily produced by CD4 T cells, acts on a subpopulation of intestinal ILC3s to promote a protective phenotype. IL-21 signaling does not affect the MHC class II-expressing ILC3 subset but promotes ILC3s that express Tbet and are poised to produce IL-22. Consistent with a protective phenotype, IL-21 deficiency dampens cytokine-induced IL-17A production. We show that exacerbated colitis develops in mice lacking the IL-21 receptor, in agreement with a protective role for IL-21 signaling on ILC3s. To our knowledge, these data reveal a novel role for IL-21 in shaping innate lymphoid cell responses in the intestine and provide one mechanism by which effector CD4 T cells can influence innate immunity.