التفاصيل البيبلوغرافية
| العنوان: |
Modeling the IL-2-Related Risk in Type One Diabetes by Selectively Lowering IL-2R Signaling in T Lymphocytes in NOD Mice |
| المؤلفون: |
Dwyer, Connor Jude |
| المساهمون: |
Thomas Malek, Alberto Pugliese, Zhibin Chen, Wasif Khan, Eleonore Beurel, Roland Tisch |
| المصدر: |
Open Access Dissertations |
| بيانات النشر: |
Scholarly Repository |
| سنة النشر: |
2017 |
| المجموعة: |
University of Miami: Scholarly Repository |
| مصطلحات موضوعية: |
IL-2, IL-2 receptor, Type 1 diabetes, Tregs, T lymphocytes |
| الوصف: |
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. |
| نوع الوثيقة: |
other/unknown material |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| الإتاحة: |
https://scholarlyrepository.miami.edu/oa_dissertations/1966Test
https://scholarlyrepository.miami.edu/cgi/viewcontent.cgi?article=2988&context=oa_dissertationsTest |
| رقم الانضمام: |
edsbas.8ADE935A |
| قاعدة البيانات: |
BASE |
