The Role of IL-15 in Activating STAT5 and Fine-Tuning IL-17A Production in CD4 T Lymphocytes

Abstract

IL-15 is an important IL-2–related cytokine whose role in Th17 cell biology has not been fully elucidated. In this study, we show that exogenous IL-15 decreased IL-17A production in Th17 cultures. Neutralization of IL-15 using an Ab led to increases in IL-17A production in Th17 cultures. Both Il15−/− and Il15r−/− T cell cultures displayed higher frequency of IL-17A producers and higher amounts of IL-17A in the supernatants compared with those of wild-type (WT) cells in vitro. IL-15 down-modulated IL-17A production independently of retinoic acid-related orphan receptor-γt, Foxp3, and IFN-γ expression. Both Th17 cells and APCs produced IL-15, which induced binding of STAT5, an apparent repressor to the Il17 locus in CD4 T cells. Also, in a model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), Il15−/− mice displayed exacerbated inflammation—correlating with increased IL-17A production by their CD4+ T cells—compared with WT controls. Exogenous IL-15 administration and IL-17A neutralization reduced the severity of EAE in Il15−/− mice. Taken together, these data indicate that IL-15 has a negative regulatory role in fine-tuning of IL-17A production and Th17-mediated inflammation.