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

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 5; pp. 1144 - 1155
• Main Authors: SUTHERLAND, Andrew P. R, VAN BELLE, Tom, WURSTER, Andrea L, SUTO, Akira, MICHAUD, Monia, ZHANG, Dorothy, GRUSBY, Michael J, VON HERRATH, Matthias
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2009
• Subjects: Animals; Antibodies; Biological and medical sciences; Care and treatment; Cloning; Control; Cytokines; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Health aspects; Insulin; Insulin - metabolism; Insulin Antibodies - metabolism; Insulin Secretion; Interleukin-21; Interleukins - deficiency; Interleukins - genetics; Interleukins - physiology; Islets of Langerhans - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Original; Pancreas - pathology; Pancreas - physiopathology; Pathogenesis; Phosphatase; Receptors, Interleukin-1 - deficiency; Receptors, Interleukin-1 - physiology; Research design; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA - genetics; Signal Transduction; Spleen - pathology; Spleen - transplantation; Type 1 diabetes; United States; Endocrinopathy; Immunopathology; Vertebrata; Mammalia; Mouse; Type 1 diabetes; Animal; Interleukin; Cytokine; Rodentia; Development; Autoimmune disease
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db08-0882

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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received August 13, 2008. Accepted January 31, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.