IL-21 Contributes to Fatal Inflammatory Disease in the Absence of Foxp3+ T Regulatory Cells

The cytokine IL-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells (Tregs). To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed the role of IL-21/IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2–dependent Foxp3 regulatory T cells and suffer from a fatal multiorgan inflammatory disease. Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2−/− mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2−/−Il21r−/− mice was reflected in reduced pancreatitis and hemolytic anemia and this was associated with distinct changes in lymphocyte effector populations, including the reduced expansion of both T follicular helper cells and Th17 cells and a compensatory increase in IL-22 in the absence of IL-21R. IL-21/IL-21R interactions were also important for the expansion of effector and memory CD8+ T cells, which were critical for the development of pancreatitis in Il2−/− mice. These findings demonstrate that IL-21 is a major target of immune system regulation.