Abstract
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.