Doctor of Philosophy (PHD)
Microbiology and Immunology (Medicine)
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The contribution of polymorphisms in IL2 and the IL-2R subunits, which are associated with several prominent autoimmune diseases including type 1 diabetes (T1D), is difficult to determine because the development of autoimmunity depends on variation of multiple genes, where the contribution of any one is small. To investigate the mechanisms whereby a modest reduction in IL-2R signaling influences diabetes in NOD mice, we co-expressed a mutant IL-2Rβ (IL-2RβY3) with wild-type IL-2Rβ selectively in T lymphocytes (designated NOD-Y3). In NOD-Y3 mice, the sensitivity of IL-2R signaling, measured as the EC50 for tyrosine phosphorylation of STAT5, was reduced approximately 2-3-fold in Tregs. Male and female NOD-Y3 mice exhibited accelerated diabetes due to intrinsic effects on multiple activities in Tregs. Bone marrow chimera and adoptive transfer experiments demonstrate that IL-2RβY3 Tregs have impaired homeostasis of lymphoid-residing central Tregs, inefficient development of highly activated effector Tregs, and are functionally less suppressive. Pancreatic IL-2RβY3 Tregs exhibited a signature consistent with an inability to optimally develop IRF4- and Blimp-1-dependent IL-10 secreting effector Tregs. NOD-Y3 mice had increased numbers of antigen-experienced CD4+ effector T cells but decreased CD8+ effector T cells. These effects appear to be largely due to impaired Tregs because adoptively transferred CD4+ Foxp3- T cells from NOD-Y3 BDC2.5 TCR transgenic 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 Tregs subsets.
IL-2; IL-2 receptor; Type 1 diabetes; Tregs; T lymphocytes
Dwyer, Connor, "Modeling the IL-2-Related Risk in Type One Diabetes by Selectively Lowering IL-2R Signaling in T Lymphocytes in NOD Mice" (2017). Open Access Dissertations. 1966.
Available for download on Wednesday, September 25, 2019