2 and 3), whereas IL-4 derived from activated NKT cells was responsible for suppressing Th1 differentiation (Fig. 4). As shown in Figs. 1–4, activated NKT cells effectively inhibited Th17 differentiation than Th1 differentiation. The generation of IL-17-producing cells was dramatically reduced by more than 70% when OT-II CD4+

T cells were co-cultured with purified NKT cells, whereas Th1 differentiation was reduced by 40%. These results are in contrast with the reports demonstrating that Th17 cells were relatively resistant to suppression by Foxp3+ Treg in several autoimmune disease models 7–9. In line with our data, NKT cells have recently been implicated Acalabrutinib clinical trial in regulating Th17-mediated diseases. In a chronic colitis model, co-transfer of DX5+ NKT cells suppressed colitis induced by CD62L+CD4+ T cells and also reduced the severity of established colitis 25. In an EAE model induced in Vα14-Jα18 TCR transgenic NOD mice, enriched invariant NKT cells inhibited disease progression, and this effect was independent of the NKT cell-mediated skewing of CD4+ T-cell differentiation from Th1 to Th2 cells 27. Additional reports have demonstrated that activation of invariant NKT cells with α-GalCer reduced disease pathogenesis in

autoimmune diabetes, encephalitis, GDC-0973 purchase and uveitis models 21, 22, 24, 28, suggesting that NKT cells can regulate Th17-mediated immune disorders. A recent report detailing the regulation of 2D2 transgenic T cell-induced autoimmune encephalitis through the inhibition of Th17 differentiation by invariant NKT cells 26 has potentiated this hypothesis. Another important point from our results is that NKT cells can suppress Th17 differentiation in the presence of the proinflammatory cytokine IL-6, which critically inhibits the development and action of Foxp3+ Treg 4–6. Additionally, natural Foxp3+ Treg can be converted into Th17 cells in the presence of IL-6 10, 11. A key obstacle preventing the use of Treg as a cell therapy is the increased local IL-6 concentration during disease 1–3,

which may result in insufficient suppression of Th17 responses by Foxp3+ Treg. Amino acid The proposed mechanisms for NKT cell-mediated immune regulation have primarily been the cytokines secreted by activated NKT cells. In NOD mice, the development of spontaneous autoimmune diabetes was suppressed with IL-4 and/or IL-10 produced from α-GalCer-activated NKT cells 21, 22. Our findings demonstrating the predominant role of IL-4 in NKT cell-mediated Th1 suppression are an extension of these reports. In this regard, NKT cell-based immunotherapies have predominantly focused on the development of new α-GalCer derivatives that could induce different cytokine spectra favoring an increased IL-4/IFN-γ ratio 29.