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

Abstract

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.

IL-2/CD25: A Long-Acting Fusion Protein That Promotes Immune Tolerance by Selectively Targeting the IL-2 Receptor on Regulatory T Cells

“…To assess diabetes in NOD mice, urine and blood glucose levels were monitored at least twice a week; mice were considered diabetes when blood glucose levels were >250 mg/dl. Pancreas lymphoid cells from NOD mice were prepared as previously described (40).…”

When worlds collide: Th17 and Treg cells in cancer and autoimmunity

“…IL-2 is critical for Treg development and function, as IL-2Rα KO, IL-2Rβ KO, and neutralization of IL-2 induce severe autoimmunity [87][88][89] . Very recent reports by Dwyer et al have further revealed that the level of IL-2 signaling is vital to proper Treg function, as chronically reduced IL-2 signaling compromised peripheral tolerance and led to accelerated onset of type 1 diabetes in NOD mice 90 . Despite its necessity for function, CD25 is not exclusively on Tregs and does not mark the Treg population as effectively in humans as it does in mice.…”

Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells

“…5 C ). Although the initial break in tolerance in type 1 diabetes seems to be due in part to defects in the Treg cell compartment, there is also evidence that the Teff cells are resistant to regulation (21) and that even a minor reduction in Treg cells due to reduced interleukin-2Rβ signaling is enough to accelerate diabetes onset (22), suggesting that reducing Teff cells may be the most effective strategy in attempting to reverse new-onset disease. This is supported by a recent study (23) showing protection from disease development in NOD mice due to gut metabolite-induced changes, either reducing the autoreactive Teff cell compartment or augmenting the Treg cell compartment, although each independently provided protection from disease, the diet that reduced the autoreactive Teff cells showed greater efficacy.…”