title: IL-21 signaling is critical for the development of type I diabetes in the NOD mouse.
abstract: IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor gamma chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans.
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 7B05, Bethesda, MD 20892-1674, USA.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Mohit
authors.initials: M
authors.lastname: Kashyap
authors.forename: Constance
authors.initials: C
authors.lastname: Robinson
authors.forename: Zuxi
authors.initials: Z
authors.lastname: Yu
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D000818:Animals; D015415:Biomarkers; D049109:Cell Proliferation; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation; D000098546:Interleukin-21
chemical_list: D015415:Biomarkers; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21
references.citation: Immunity. 2002 Apr;16(4):559-69
references.pmid: 11970879
references.citation: J Immunol. 2007 Mar 15;178(6):3822-30
references.pmid: 17339481
references.citation: J Exp Med. 2008 Jan 21;205(1):207-18
references.pmid: 18195074
references.citation: Diabetes. 2002 Dec;51 Suppl 3:S478-83
references.pmid: 12475793
references.citation: Nat Immunol. 2007 Sep;8(9):967-74
references.pmid: 17581537
references.citation: Nat Genet. 2007 Mar;39(3):329-37
references.pmid: 17277778
references.citation: Science. 2002 Nov 22;298(5598):1630-4
references.pmid: 12446913
references.citation: Diabetes. 2008 Jan;57(1):113-23
references.pmid: 17928397
references.citation: Nature. 2005 May 26;435(7041):452-8
references.pmid: 15917799
references.citation: Diabetes. 2003 Feb;52(2):327-34
references.pmid: 12540604
references.citation: Gene. 1997 Feb 7;185(2):159-68
references.pmid: 9055810
references.citation: Diabetes. 2007 Jan;56(1):34-40
references.pmid: 17192462
references.citation: J Exp Med. 2005 Jan 3;201(1):139-48
references.pmid: 15630141
references.citation: Nature. 2007 Jul 26;448(7152):480-3
references.pmid: 17581589
references.citation: J Immunol. 2007 Mar 1;178(5):2827-34
references.pmid: 17312126
references.citation: Cell. 1993 Apr 9;73(1):147-57
references.pmid: 8462096
references.citation: Nature. 2000 Nov 2;408(6808):57-63
references.pmid: 11081504
references.citation: J Immunol. 2004 Nov 1;173(9):5361-71
references.pmid: 15494482
references.citation: Arthritis Rheum. 2007 Apr;56(4):1152-63
references.pmid: 17393408
references.citation: Immunity. 2000 Apr;12(4):431-40
references.pmid: 10795741
references.citation: Cell. 2004 Apr 16;117(2):265-77
references.pmid: 15084263
references.citation: Physiol Genomics. 2005 Apr 14;21(2):201-11
references.pmid: 15671250
references.citation: Diabetes. 2002 Feb;51(2):339-46
references.pmid: 11812740
references.citation: Nature. 2007 Jul 26;448(7152):484-487
references.pmid: 17581588
references.citation: Cell Mol Life Sci. 2005 Nov;62(22):2658-68
references.pmid: 16261264
references.citation: Eur J Immunol. 2006 Jan;36(1):216-23
references.pmid: 16358360
references.citation: Annu Rev Immunol. 2008;26:57-79
references.pmid: 17953510
references.citation: Annu Rev Immunol. 2005;23:447-85
references.pmid: 15771578