1%) compared with control mice (32±1.4%). These TSA HDAC data suggest that the enhanced incidence of diabetes in mice reconstituted with CD4− iNKT cells is due to the increased frequency of diabetogenic BDC2.5 T cells. Indeed, the frequency of pathogenic

BDC2.5 T cells is probably a key parameter controlling the development of diabetes, since non-diabetic mice reconstituted with CD4+ iNKT cells contained only 0.9±0.2% and 12±6.4% of BDC2.5 T cells in their PLNs and pancreas, respectively. Our results highlight the pathogenic role of CD4− iNKT cells. To demonstrate the key role of IL-17, produced by iNKT17 cells, we treated mice with an anti-IL-17 antibody. Importantly, this treatment abolished the deleterious role of CD4− iNKT cells whereas it does not alter the incidence of diabetes induced by BDC2.5 T cells alone (Fig. 4B). Altogether, our results show that CD4− iNKT cells containing iNKT17 cells exacerbate the development of diabetes in an IL-17-dependent manner. It has been well established that activation of iNKT cells by repeated αGalCer injections prevents the development of diabetes in NOD mice 8, 10, 15. Autoimmunity prevention correlated with the ability of αGalCer to induce click here iNKT cell anergy and to strongly

suppress their IFN-γ production while IL-4 production was less inhibited 33. Interestingly, we have observed that αGalCer treatment suppressed not only IFN-γ by iNKT cells but also their IL-17 production whereas it does not inhibit IL-10 production (Fig. 5). This inhibition of IL-17 production could be critical in the protective role of αGalCer treatment. Our study reveals that NOD mice exhibit a high frequency of iNKT17 cells, which produce IL-17 in the pancreas and can exacerbate diabetes development upon cell transfer. Phloretin This study suggests that IL-17 can participate in the pathology of type 1 diabetes. The role of IL-17 in autoimmune diabetes was first suggested by the low IL-17 production observed in NOD mice protected against the disease after treatment with a modified self-peptide 25. More recent

studies showed that IL-17 neutralization with specific antibodies prevents the development of diabetes in NOD mice 27. Different immune cell populations can secrete IL-17 34. The role of Th17 cells in diabetes remains unclear. Indeed the induction of the disease in NOD SCID mice after transfer of in vitro polarized Th17 anti-islet T cells was abolished by anti-IL-17 treatment in one study but not in two others 25, 26. It has been reported that IL-17-producing γδT cells do not exacerbate diabetes upon co-transfer into NOD/SCID mice 35. iNKT17 cells represent a new subset of IL-17-producing cells 19 and we observed an increased frequency of this cell population in NOD mice as compared with non-autoimmune C57BL/6 mice. iNKT17 cells from NOD and C57BL/6 mice exhibit a similar phenotype, mainly CD4− and NK1.1−.