The authors declare no financial or commercial conflict of interest. Table S1. Primer sequences used for immunoscope analysis. Table S2. Primer sequences used for immunoscope analysis. “
“CD4+ T lymphocytes are required to induce spontaneous autoimmune diabetes in the NOD mouse. Since pancreatic β cells

upregulate Fas expression upon exposure to pro-inflammatory cytokines, we studied whether the MLN8237 diabetogenic action of CD4+ T lymphocytes depends on Fas expression on target cells. We assayed the diabetogenic capacity of NOD spleen CD4+ T lymphocytes when adoptively transferred into a NOD mouse model combining: (i) Fas-deficiency, (ii) FasL-deficiency, and (iii) SCID mutation. We found that CD4+ T lymphocytes require Fas expression in the recipients’ target cells to induce diabetes. IL-1β has been described as a key cytokine involved in Fas upregulation on mouse β cells. We addressed whether CD4+ T cells Doxorubicin concentration require IL-1β to induce diabetes. We also studied spontaneous diabetes onset in NOD/IL-1 converting enzyme-deficient mice, in NOD/IL-1β-deficient mice, and CD4+ T-cell adoptively transferred diabetes into NOD/SCID IL-1β-deficient mice. Neither IL-1β nor IL-18 are required for either spontaneous or CD4+ T-cell adoptively transferred diabetes. We conclude that CD4+ T-cell-mediated β-cell damage in autoimmune

diabetes depends on Fas expression, but not on IL-1β unveiling the existing redundancy regarding the cytokines involved in Fas upregulation on NOD β cells in vivo. Autoimmune diabetes (type 1 diabetes mellitus or T1D) is a T-cell-mediated condition characterized by the selective destruction of insulin-producing

β cells 1. Three major effector pathways for β-cell destruction have been proposed for T1D: the Fas/FasL 2 and perforin 3 pro-apoptotic pathways, and cytokine-induced β-cell death via iNOS 4. The most extensively pursued mechanism this website has been the Fas(CD95)/FasL(CD95L) pathway, which seems to be one of the main pathways involved in cytokine-induced β-cell death 5, 6. The Fas death receptor belongs to the TNF receptor family, and trimerizes once engaged by its trimeric ligand, FasL, a member of the TNF family. Fas trimerization triggers the death cascade by inducing extrinsic apoptosis. Fas expression on β cells is upregulated by IL-1β in conjunction with IFN-γ in mice 6–8. Moreover, chemical depletion of macrophages, the main producers of IL-1β upon activation, abrogates diabetes onset 9 in NOD mice, one of the most studied animal models for T1D 1. In addition, IL-1β is involved in NO-mediated β-cell death by necrosis 10, 11. However, apoptosis and not necrosis has been reported to be the main mechanism responsible for spontaneous diabetes onset in T1D 10, 12.