The cytokine interleukin-2 (IL-2) is critical for the functions of regulatory T cells (T_regs). The contribution of polymorphisms in the gene encoding the IL-2 receptor α subunit (IL2RA), which are associated with type 1 diabetes, is difficult to determine because autoimmunity depends on variations in multiple genes, where the contribution of any one gene product is small. We investigated the mechanisms whereby a modest reduction in IL-2R signaling selectively in T lymphocytes influenced the development of diabetes in the NOD mouse model. The sensitivity of IL-2R signaling was reduced by about two- to threefold in T_regs from mice that coexpressed wild-type IL-2Rβ and a mutant subunit (IL-2Rβ^Y3) with reduced signaling (designated NOD-Y3). Male and female NOD-Y3 mice exhibited accelerated diabetes onset due to intrinsic effects on multiple activities in T_regs Bone marrow chimera and adoptive transfer experiments demonstrated that IL-2Rβ^Y3 T_regs resulted in impaired homeostasis of lymphoid-residing central T_regs and inefficient development of highly activated effector T_regs and that they were less suppressive. Pancreatic IL-2Rβ^Y3 T_regs showed impaired development into IL-10-secreting effector T_regs The pancreatic lymph nodes and pancreases of NOD-Y3 mice had increased numbers of antigen-experienced CD4⁺ effector T cells, which was largely due to impaired T_regs, because adoptively transferred pancreatic autoantigen-specific CD4⁺ Foxp3^- T cells from NOD-Y3 mice did not accelerate diabetes in NOD.SCID recipients. Our study indicates that the primary defect associated with chronic, mildly reduced IL-2R signaling is due to impaired T_regs that cannot effectively produce and maintain highly functional tissue-seeking effector T_reg subsets.

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