IFN-γ receptor deficiency prevents diabetes induction by diabetogenic CD4+, but not CD8+, T cells.

IFN-γ is generally believed to be important in the autoimmune pathogenesis of type 1 diabetes (T1D). However, the development of spontaneous β-cell autoimmunity is unaffected in NOD mice lacking expression of IFN-γ or the IFN-γ receptor (IFNγR), bringing into question the role IFN-γ has in T1D. In the current study, an adoptive transfer model was employed to define the contribution of IFN-γ in CD4+ versus CD8+ T cell-mediated β-cell autoimmunity. NOD.scid mice lacking expression of the IFNγR β chain (NOD.scid.IFNγRBnull) developed diabetes following transfer of β cell-specific CD8+ T cells alone. In contrast, β cell-specific CD4+ T cells alone failed to induce diabetes despite significant infiltration of the islets in NOD.scid.IFNγRBnull recipients. The lack of pathogenicity of CD4+ T-cell effectors was due to the resistance of IFNγR-deficient β cells to inflammatory cytokine-induced cell death. On the other hand, CD4+ T cells indirectly promoted β-cell destruction by providing help to CD8+ T cells in NOD.scid.IFNγRBnull recipients. These results demonstrate that IFN-γR may play a key role in CD4+ T cell-mediated β-cell destruction.