| First Author | Dwyer CJ | Year | 2017 |
| Journal | Sci Signal | Volume | 10 |
| Issue | 510 | PubMed ID | 29259102 |
| Mgi Jnum | J:259995 | Mgi Id | MGI:6141645 |
| Doi | 10.1126/scisignal.aam9563 | Citation | Dwyer CJ, et al. (2017) Altered homeostasis and development of regulatory T cell subsets represent an IL-2R-dependent risk for diabetes in NOD mice. Sci Signal 10(510) |
| abstractText | 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 alpha 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-2Rbeta and a mutant subunit (IL-2Rbeta(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 Tregs Bone marrow chimera and adoptive transfer experiments demonstrated that IL-2Rbeta(Y3) 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-2Rbeta(Y3) 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. |
