Interleukin-21 drives intestinal inflammation by bridging the adaptive and innate immune compartments (P3181)

Abstract

Abstract Th17 CD4 T cells have been cast as pathogenic in the context of many autoimmune diseases, including Inflammatory Bowel Disease (IBD); however, the mechanism for this pathogenicity has yet to be elucidated. Based on the observation that IL-21 expression is increased in biopsies from patients with ulcerative colitis compared to healthy controls, we posit that IL-21 produced by Th17 cells mediates inflammation in the intestine. Using models of both spontaneous and CD4 T cell-dependent colitis, we show that a large number of IL-21-producing CD4 T cells are present in the intestines of mice with colitis and importantly, that IL-21 production is required for full disease progression. We find that although IL-21-/- CD4 T cells are unable to initiate disease, they produce elevated levels of IL-17A and IL-17F and are not selectively converted into Foxp3+ regulatory T cells, indicating that IL-21 is both crucial to the induction of colitis and surprisingly, is not acting via effects on the activation and differentiation of T cells. In direct support of this idea, IL-21R-/- CD4 T cells are capable of inducing disease unlike their IL-21-/- counterparts. In fact, our data demonstrate that IL-21 has an impact on the innate lymphoid cell compartment, which has previously been implicated in IBD pathogenesis. Taken together, our data show an important and previously unrecognized role for IL-21 that links CD4 T cells to innate lymphoid cells in the induction of chronic intestinal inflammation.