Invariant NKT cells regulate experimental autoimmune uveitis through inhibition of Th17 differentiation

Although NKT cells have been implicated in diverse immunomodulatory responses, the effector mechanisms underlying the NKT cell-mediated regulation of pathogenic T helper cells are not well understood. Here, we show that invariant NKT cells inhibited the differentiation of CD4(+) T cells into Th17 cells both in vitro and in vivo. The number of IL-17-producing CD4(+) T cells was reduced following co-culture with purified NK1.1(+)TCR(+) cells from WT, but not from CD1d(-/-) or J alpha 18(-/-), mice. Co-cultured NKT cells from either cytokine-deficient (IL-4(-/-), IL-10(-/-), or IFN-gamma(-/-)) or WT mice efficiently inhibited Th17 differentiation. The contact-dependent mechanisms of NKT cell-mediated regulation of Th17 differentiation were confirmed using transwell co-culture experiments. On the contrary, the suppression of Th1 differentiation was dependent on IL-4 derived from the NKT cells. The in vivo regulatory capacity of NKT cells on Th17 cells was confirmed using an experimental autoimmune uveitis model induced with human IRBP1-20 (IRBP, inter-photoreceptor retinoid-binding protein) peptide. NKT cell-deficient mice (CD1d(-/-) or J alpha 18(-/-) ) demonstrated an increased disease severity, which was reversed by the transfer of WT or cytokine-deficient (IL-4(-/-), IL-10(-/-), or IFN-gamma(-/-)) NKT cells. Our results indicate that invariant NKT cells inhibited autoimmune uveitis predominantly through the cytokine-independent inhibition of Th17 differentiation.