β-Cell–Specific IL-2 Therapy Increases Islet Foxp3+Treg and Suppresses Type 1 Diabetes in NOD Mice
- Mark C. Johnson1,
- Alaina L. Garland1,
- Sarah C. Nicolson2,3,
- Chengwen Li2,3,
- R. Jude Samulski2,3,
- Bo Wang1 and
- Roland Tisch1,4⇑
- 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- 2Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- 3Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- 4UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Corresponding author: Roland Tisch, .
Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3–expressing regulatory T cells (Foxp3+Tregs). Dysregulation of the IL-2–IL-2 receptor axis is associated with aberrant Foxp3+Tregs and T cell–mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3+Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3+Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3+Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3+Tregs in dsAAVmIP-IL2–treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell–specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell–specific IL-2 expands an islet-resident Foxp3+Tregs pool that effectively suppresses ongoing type 1 diabetes long term.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0669/-/DC1.
- Received April 25, 2013.
- Accepted July 16, 2013.
- © 2013 by the American Diabetes Association.
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