IL-27 limits CD4+ TH17 cell development in vitro and during inflammatory responses in the CNS. However, whether IL-27-IL-27R interactions regulate the homeostasis or function of CD4+ T cell populations in the intestine is unknown. To test this, we examined CD4 + T cell populations in the intestine of wild-type and IL-27R -/- mice. Naive IL-27R-/- mice exhibited a selective decrease in the frequency of IFN-γ producing CD4+ T H1 cells and an increase in the frequency of TH17 cells in gut-associated lymphoid tissues. Associated with elevated expression of IL-17A, IL-27R-/- mice exhibited earlier onset and significantly increased severity of clinical disease compared with wild-type controls in a murine model of intestinal inflammation. Rag-/-/IL-27R-/- mice were also more susceptible than Rag-/- mice to development of dextran sodium sulfate-induced intestinal inflammation, indicating an additional role for IL-27-IL-27R in the regulation of innate immune cell function. Consistent with this, IL-27 inhibited proinflammatory cytokine production by activated neutrophils. Collectively, these data identify a role for IL-27-IL-27R interaction in controlling the homeostasis of the intestinal T cell pool and in limiting intestinal inflammation through regulation of innate and adaptive immune cell function.