The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes

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.