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PMID: 19208913 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Diabetes ·Vol. 58 ·No. 5 ·2009-05-00 ·Pages 1144-55

Sutherland AP, Van Belle T, Wurster AL, Suto A, Michaud M, Zhang D, Grusby MJ, von Herrath M

Abstract

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. We generated IL-21R-deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic beta-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes. 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 beta-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-gamma, 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 beta-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD x C57Bl/6 backgrounds. 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.

MeSH Terms
Animals Diabetes Mellitus, Type 1/genetics,pathology,physiopathology Insulin/metabolism Insulin Antibodies/metabolism Insulin Secretion Interleukins/deficiency,genetics,physiology Islets of Langerhans/metabolism Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Knockout Pancreas/pathology,physiopathology RNA/genetics Receptors, Interleukin-1/deficiency,physiology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Spleen/pathology,transplantation
Chemicals
Insulin Insulin Antibodies Interleukins Receptors, Interleukin-1 RNA interleukin-21
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Sutherland Andrew P R
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
Van Belle Tom
Wurster Andrea L
Suto Akira
Michaud Monia
Zhang Dorothy
Grusby Michael J
von Herrath Matthias
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Article Info
Journal
Diabetes
Abbr.
Diabetes
ISSN
1939-327X
DOI
10.2337/db08-0882
Published
2009-05-00
Epub
2009-00-10
Pages
1144-55
Language
English
Region
United States
NLM ID
0372763
PMCID
PMC2671036
Subset
IM
External Links
PubMed source DOI: 10.2337/db08-0882 PMC Full Text View journal details
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