GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity

Abstract

Glucocorticoid-induced TNFR family related gene (GITR) is a member of the TNFR superfamily that is expressed on cells of the immune system. Although the protective and pathogenic roles of GITR in T cell immunity are well characterized, the role of GITR in innate immunity in the intestinal tissues has not been well clarified. In this study, using a dextran sulfate sodium (DSS)-induced colitis model in mice, we found that GITR-deficiency rendered mice more susceptible to acute intestinal inflammation and that a significantly higher number of activated natural killer (NK) cells was accumulated in the colonic lamina propria of Gitr−/− mice as compared to wild-type mice. Additionally, Rag2−/− Gitr−/− mice, which lack T cells but have NK cells, also displayed more severe colonic inflammation than Rag2−/− mice. In contrast, an anti-GITR agonistic antibody significantly alleviated colitis in Rag2−/− mice. Engagement of GITR inhibited IL-15-mediated activating signaling events in NK cells, which include cell activation and proliferation, and production of cytokines and cytotoxic granules. Taken together, our results provide the first evidence that GITR negatively controls intestinal inflammation through NK cell functions.