In vivo diabetogenic action of CD4+ T lymphocytes requires Fas expression and is independent of IL-1 and IL-18

CD4(+) T lymphocytes are required to induce spontaneous autoimmune diabetes in the NOD mouse. Since pancreatic beta cells upregulate Fas expression upon exposure to pro-inflammatory cytokines, we studied whether the 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-1 beta has been described as a key cytokine involved in Fas upregulation on mouse b cells. We addressed whether CD4(+) T cells require IL-1 beta to induce diabetes. We also studied spontaneous diabetes onset in NOD/IL-1 converting enzyme-deficient mice, in NOD/IL-1 beta-deficient mice, and CD4(+) T-cell adoptively transferred diabetes into NOD/SCID IL-1 beta-deficient mice. Neither IL-1 beta nor IL-18 are required for either spontaneous or CD4(+) T-cell adoptively transferred diabetes. We conclude that CD4(+) T-cell-mediated beta-cell damage in autoimmune diabetes depends on Fas expression, but not on IL-1 beta unveiling the existing redundancy regarding the cytokines involved in Fas upregulation on NOD beta cells in vivo.