IL-9-producing invariant NKT cells protect against DSS-induced colitis in an IL-4-dependent manner

Although the T-helper type 9 (Th9) subset has recently been revisited, interleukin (IL)-9-producing invariant natural killer T (iNKT) cells remain poorly characterized. Moreover, whether IL-9-producing iNKT cells regulate colitis is unknown. Here, we investigated functions of IL-9-producing iNKT cells in dextran sulfate sodium (DSS)-induced colitis. Wildtype (WT) mice attenuated colitis compared to J alpha 18(-/-) mice, which were restored by the adoptive transfer of WT, but not IL-4-deficient iNKT cells. IL-4-deficient iNKT cells failed to produce IL-9, which was reversed by recombinant IL-4. Furthermore, iNKT cells, pre-incubated with anti-CD3 (+) CD28 monoclonal antibodies and IL-4 + tumor growth factor (TGF)-beta (IL-9 (+) iNKT), suppressed colitis in J alpha 18(-/-) mice, whereas pre-incubated IL-4-deficient iNKT cells did not. IL-9 blockade reversed IL-9 + iNKT cell-mediated colitis by increasing colonic IL-17A and interferon (IFN)-gamma transcripts, but decreasing IL-9, IL-10, TGF-beta, PU. 1, IFN regulatory factor 4, and signal transducer and activator of transcription 5 in J alpha 18(-/-) mice. In conclusion, IL-9-producing iNKT cells protect against DSS-induced colitis through IFN-gamma and IL-17A suppression, but IL-10 and TGF-beta enhancement, depending on the IL-4 production by iNKT cells.