IL-17 inhibits human Th1 differentiation through IL-12Rβ2 downregulation

Th17 cells are critical in adaptive immunity and autoimmune disease. The polarized development of Th17, Th1 and Th2 cells is dependent on counterregulatory effects on each other. Whereas IFN-γ inhibits Th17 development, the effect of IL-17 in human Th1 development is not known. We report a novel negative regulatory role of IL-17 on IL-12Rβ2 expression associated with reduced IL-12 responsiveness. IL-17 decreased IL-12-induced IFN-γ expression in PBMC and developing Th1 cells, associated with a selective reduction in IL-12Rβ2, and not IL-23R, IL-12Rβ1 or T-bet. Counterregulatory effects of human Th17 on Th1 lineage cytokines may contribute to lineage divergence. In autoimmune disease, IL-17 may reinforce its own developmental programme by reducing IL-12 responsiveness, thus limiting inhibitory effects of IFN-γ on Th17 development.