Spontaneous diabetes in NOD/IL-1β KO mice is indistinguishable to that of WT and heterozygous littermates ALK inhibitor (p>0.6, log-rank test) (Fig. 4). Additionally, IL-1β deficient NOD/SCID recipient mice are equally susceptible to autoimmune diabetes as IL-1β sufficient NOD/SCID recipient mice when adoptively transferred with either total NOD spleen cells

(p>0.4, log-rank test) (Fig. 5) or purified CD4+ T cells (p>0.5, log-rank test ) (Fig. 6). We conclude from these results that, contrary to our expectations, IL-1β is essential for neither spontaneous nor transferred diabetes. Here we show that Fas expression is required for the adoptive transfer of diabetes by CD4+ T cells. CD4+ T cells are essential effectors in the induction of islet infiltration and β-cell death 19, but so far no clear link has been delineated between CD4+ T cells and the molecular pathway triggered to cause the destruction of β cells. We have observed BMS-777607 mouse that primed CD4+ T cells require the presence of Fas on NOD/SCID recipients to cause T1D. The expression of Fas within islets has mostly been associated with intra-islet macrophages, dendritic cells and to a lesser extent to infiltrating lymphocytes 31. Fas expression is, however, upregulated on islet

cells upon exposure to cytokines 6–8. Fas has been detected by cytometric analysis of β cells in in vivo models of accelerated, but not spontaneous, diabetes 32. Two recent reports have revealed that Fas is actually necessary to induce β-cell apoptosis in NOD mice 16, 17. Although in pancreatic islets from Fas-deficient NOD/SCID lpr/lpr mice there are other cell types in addition to pancreatic β cells, which are also deprived of Fas expression,

mostly dendritic cells and macrophages 31. sublethally irradiated NOD mice, when adoptively transferred with spleen cells from either pre-diabetic or diabetic NOD donor do not develop diabetes 2. In this experimental O-methylated flavonoid approach, donor splenocytes included Fas-sufficient macrophages, dendritic cells and other hematopoietic subpopulations that could replace the Fas-deficient recipient cell types. Nonetheless, total spleen cells from a Fas-sufficient donor are not able to transfer diabetes to Fas-deficient sub lethal irradiate NOD recipients, which clearly suggests that Fas deficiency on β cells is responsible for the absence of diabetes onset. Moreover, in our experimental setting, the adoptively transferred CD4+ T cells are already primed, and therefore only require proper antigen presentation by local antigen presenting cells (dendritic cells and macrophages) to activate their effector functions. Our results are consistent with a scenario in which Fas-deficiency on target pancreatic β cells, and not on other cell types (macrophages and dendritic cells), is responsible for the impaired diabetes induction. Our results are supported by those from Nakayama et al.