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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 Jα18−/−, mice. Co‐cultured NKT cells from either cytokine‐deficient (IL‐4−/−, IL‐10−/−, or IFN‐γ−/−) 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, interphotoreceptor retinoid‐binding protein) peptide. NKT cell‐deficient mice (CD1d−/− or Jα18−/−) demonstrated an increased disease severity, which was reversed by the transfer of WT or cytokine‐deficient (IL‐4−/−, IL‐10−/−, or IFN‐γ−/−) NKT cells. Our results indicate that invariant NKT cells inhibited autoimmune uveitis predominantly through the cytokine‐independent inhibition of Th17 differentiation.