Publication Date

2017-09-25

Availability

Embargoed

Embargo Period

2019-09-25

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2017-08-24

First Committee Member

Thomas Malek

Second Committee Member

Alberto Pugliese

Third Committee Member

Zhibin Chen

Fourth Committee Member

Wasif Khan

Fifth Committee Member

Eleonore Beurel

Sixth Committee Member

Roland Tisch

Abstract

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.

Keywords

IL-2; IL-2 receptor; Type 1 diabetes; Tregs; T lymphocytes

Available for download on Wednesday, September 25, 2019

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