Altered homeostasis and development of regulatory T cell subsets represent an IL-2R-dependent risk for diabetes in NOD mice.

The cytokine interleukin-2 (IL-2) is critical for the functions of regulatory T cells (T). The contribution of polymorphisms in the gene encoding the IL-2 receptor α subunit (), 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 from mice that coexpressed wild-type IL-2Rβ and a mutant subunit (IL-2Rβ) 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 Bone marrow chimera and adoptive transfer experiments demonstrated that IL-2Rβ T resulted in impaired homeostasis of lymphoid-residing central T and inefficient development of highly activated effector T and that they were less suppressive. Pancreatic IL-2Rβ T showed impaired development into IL-10-secreting effector T 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, 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 that cannot effectively produce and maintain highly functional tissue-seeking effector T subsets.