Research ArticleImmunology

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

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Sci. Signal.  19 Dec 2017:
Vol. 10, Issue 510, eaam9563
DOI: 10.1126/scisignal.aam9563

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IL-2 signaling and autoimmunity

Regulatory T cells (Tregs) suppress autoreactive effector T cells to prevent the occurrence of autoimmune diseases, such as type 1 diabetes (T1D). The cytokine interleukin-2 (IL-2) is critical for the development and homeostasis of Treg subsets. Polymorphisms in the genes encoding IL-2 and its receptor subunits are associated with an increased risk of developing autoimmunity. To examine the effect of decreased IL-2 signaling, Dwyer et al. expressed a signaling-defective mutant IL-2 receptor (IL-2RβY3) in T cells in NOD mice, a model of T1D. Compared to NOD mice expressing wild-type IL-2Rβ, those expressing IL-2RβY3 in their T cells had accelerated onset of T1D. This was associated with a decrease in the numbers and suppressive activity of different Treg subsets and in the infiltration of autoreactive effector T cells into the pancreas. Together, these data suggest that the use of low-dose IL-2 to therapeutically modulate different Treg subsets in the context of autoimmune disease should be evaluated.


The cytokine interleukin-2 (IL-2) is critical for the functions of regulatory T cells (Tregs). 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 Tregs from mice that coexpressed wild-type IL-2Rβ and a mutant subunit (IL-2RβY3) with reduced signaling (designated NOD-Y3). Male and female NOD-Y3 mice exhibited accelerated diabetes onset due to intrinsic effects on multiple activities in Tregs. Bone marrow chimera and adoptive transfer experiments demonstrated that IL-2RβY3 Tregs resulted in impaired homeostasis of lymphoid-residing central Tregs and inefficient development of highly activated effector Tregs and that they were less suppressive. Pancreatic IL-2RβY3 Tregs showed impaired development into IL-10–secreting effector Tregs. 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 Tregs, 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 Tregs that cannot effectively produce and maintain highly functional tissue-seeking effector Treg subsets.

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