Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice

Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice Andrew P.R. Sutherland 1 , 2 , Tom Van Belle 3 , Andrea L. Wurster 1 , Akira Suto 1 , Monia Michaud 1 , Dorothy Zhang 1 , Michael J. Grusby 1 , 4 and Matthias von Herrath 3 1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts; 2 John Curtin School of Medical Research, Australian National University, Canberra, Australia; 3 Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California; 4 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts. Corresponding author: Matthias von Herrath, matthias{at}liai.org , and Michael Grusby, mgrusby{at}hsph.harvard.edu . A.P.R.S. and T.V.B. contributed equally to this work. Abstract OBJECTIVE Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes. 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 type 1 diabetes. RESULTS Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R −/− NOD is normal and 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, overexpression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds. CONCLUSIONS This work provides demonstration of the essential prodiabetogenic 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 type 1 diabetes.