β-Cell–Specific IL-2 Therapy Increases Islet Foxp3+Treg and Suppresses Type 1 Diabetes in NOD Mice

  1. Roland Tisch1,4
  1. 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  2. 2Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  3. 3Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  4. 4UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  1. Corresponding author: Roland Tisch, rmtisch{at}med.unc.edu.

Abstract

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.

Footnotes

  • Received April 25, 2013.
  • Accepted July 16, 2013.

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  1. Diabetes vol. 62 no. 11 3775-3784
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