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


METHODS
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.


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 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.


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.
Sutherland
Andrew P R
AP
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
Van Belle
Tom
T
Wurster
Andrea L
AL
Suto
Akira
A
Michaud
Monia
M
Zhang
Dorothy
D
Grusby
Michael J
MJ
von Herrath
Matthias
M
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism; D007330:Insulin Antibodies / Q000378:metabolism; D000078790:Insulin Secretion; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology / Q000503:physiopathology; D012313:RNA / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology / Q000637:transplantation; D000098546:Interleukin-21
D007328:Insulin; D007330:Insulin Antibodies; D007378:Interleukins; D017472:Receptors, Interleukin-1; D012313:RNA; D000098546:Interleukin-21