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

Connor J. Dwyer, Allison L Bayer, Carmen Fotino, Liping Yu, Cecilia Cabello-Kindelan, Natasha C. Ward, Kevin H. Toomer, Zhibin Chen, Thomas Malek

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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 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-2R and a mutant subunit (IL-2RY3) 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-2RY3 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-2RY3 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.

Original languageEnglish (US)
Article numbereaam9563
JournalScience Signaling
Volume10
Issue number510
DOIs
StatePublished - Dec 19 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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