Type 1 diabetes (T1D) is an autoimmune disease mediated by self-reactive T cells. This complex disorder depends on genetic risk factors and environmental triggers. Polymorphisms in IL-2 or IL-2R subunits are important genetic risks that are associated with T1D. In NOD mice, polymorphisms in IL-2 at the Idd3 locus results in lower IL-2 production leading to impaired Tregs. Conceptually, this result implies that defective IL-2R signaling at the level of Tregs represents a genetic risk in T1D. Nevertheless, how altered IL-2R signaling in Tregs contribute to T1D is poorly understood. Treatment of mice with low dose IL-2 suppresses T1D in NOD mice. The basis for this improved outcome is poorly understood other than an obvious association with increased production of Tregs. Our recent work offers an initial mechanistic insight for the success of low dose IL-2 therapy for tolerance induction and provides some of the rationale for the proposed studies. By developing mouse models that vary in IL-2R signaling strength, Treg development and homeostasis were found to require low IL-2R signaling. Thus, critical IL-2-dependent properties in Tregs are positively affected by low dose IL-2. However, other than induction of Foxp3 and CD25, little is known concerning the mechanisms activated in Tregs by weak IL-2R signaling. To add another layer of complexity, we have defined other activities in Tregs that require more extensive signaling, including the development of Treg subsets. An important hypothesis for this proposal is that key functional and molecular properties of Tregs will vary asymmetrically in relationship to IL-2R signaling intensity. Accordingly, those Treg activities dependent on high IL-2R signaling will initially be impaired. These types of activities might affect Treg homeostasis but also likely interfere with Treg function, including their development into a highly active suppressive subset. Chronic low IL-2R signaling will then impair other Treg activities that lead to T1D. Major objectives of this proposal are to systemically identify the full range of IL-2-dependent properties that vary in Tregs as a consequence of impaired IL-2R signaling or after IL-2 immunotherapy. Such information will provide a foundation to better understand the underlying IL-2- related risk for autoimmune disease and the basis for successful IL-2-based tolerogenic therapy in general and for T1D in particular. To test our hypotheses and achieve our objectives, the following aims are proposed: 1) To determine the extent that impaired IL-2R signaling in NOD mice alters the function of Treg and Teff cells and accounts for the genetic susceptibility to T1D~ 2) to establish the extent the development and stability of Treg subsets depend on IL-2R signaling and the functional relevance of activated Tregs to suppress autoimmunity~ and 3) to investigate the basis by which enhanced IL-2R signaling leads to tolerance induction for suppression of T1D in NOD mice.

Public Health Relevance

Defective IL-2R signaling is associated with Tregs in T1D patients. Low dose IL-2 therapy boosts Tregs and promotes tolerance in several human disorders with uncontrolled self- reactivity. The knowledge gain from the proposed studies may define: 1) an underlying IL-2- related risk for T1D, 2) new biomarkers predictive of the onset or severity of T1D, and 3) the mechanism, including cellular and molecular targets, predictive of successful therapy of T1D. As the NOD model resembles human T1D, there is the potential that such information may be directly translated to individuals with T1D.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093866-02
Application #
8554761
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2012-09-27
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$321,129
Indirect Cost
$111,241
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Yuan, Xiaomei; Cheng, Guoyan; Malek, Thomas R (2014) The importance of regulatory T-cell heterogeneity in maintaining self-tolerance. Immunol Rev 259:103-14
Hodgkinson, Victoria; Petris, Michael J (2012) Copper homeostasis at the host-pathogen interface. J Biol Chem 287:13549-55