IL-21 is required for the development of type 1 diabetes in NOD mice

  1. Andrew P. R. Sutherland1,2,
  2. Tom Van Belle3,
  3. Andrea L. Wurster1,4,
  4. Akira Suto1,5,
  5. Monia Michaud1,
  6. Dorothy Zhang1,
  7. Michael J. Grusby (mgrusby{at}hsph.harvard.edu)1,6 and
  8. Matthias von Herrath (matthias{at}liai.org)3
  1. 1 Department of Immunology and Infectious Diseases, Harvard School of Public Health
  2. 2 John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia
  3. 3 Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology
  4. 4 Current address: National Institute on Aging, Laboratory of Cellular and Molecular Biology
  5. 5 Current address: Department of Molecular Genetics, Graduate School of Medicine, Chiba University
  6. 6 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School

    Abstract

    Objective: IL-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes (T1D) via the unique biology of the Non-Obese Diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in T1D.

    Research Design and Methods: We generated IL-21R deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic β-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in T1D.

    Results: Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies and onset of T1D. The lymphoid compartment in IL-21R−/− NOD is normal, does not contain an increased regulatory T cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T cells in IL-21R−/− NOD by transfer experiments. Conversely, over-expression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, MCP-1, MCP-2, IP-10, in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous T1D in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds.

    Conclusions: This work provides demonstration of the essential pro-diabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human T1D.

    Footnotes

      • Received August 13, 2008.
      • Accepted February 1, 2009.

    This Article

    1. Published online before print February 10, 2009, doi: 10.2337/db08-0882
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