title: Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells.
abstract: Polymorphisms in MHC class II molecules, in particular around β-chain position-57 (β57), afford susceptibility/resistance to multiple autoimmune diseases, including type 1 diabetes, through obscure mechanisms. Here, we show that the antidiabetogenic MHC class II molecule I-A(b) affords diabetes resistance by promoting the differentiation of MHC-promiscuous autoreactive CD4(+) T cells into disease-suppressing natural regulatory T cells, in a β56-67-regulated manner. We compared the tolerogenic and antidiabetogenic properties of CD11c promoter-driven transgenes encoding I-A(b) or a form of I-A(b) carrying residues 56-67 of I-Aβ(g7) (I-A(b-g7)) in wild-type nonobese diabetic (NOD) mice, as well as NOD mice coexpressing a diabetogenic and I-A(g7)-restricted, but MHC-promiscuous T-cell receptor (4.1). Both I-A transgenes protected NOD and 4.1-NOD mice from diabetes. However, whereas I-A(b) induced 4.1-CD4(+) thymocyte deletion and 4.1-CD4(+)Foxp3(+) regulatory T-cell development, I-A(b-g7) promoted 4.1-CD4(+)Foxp3(+) Treg development without inducing clonal deletion. Furthermore, non-T-cell receptor transgenic NOD.CD11cP-I-A(b) and NOD.CD11cP-IA(b-g7) mice both exported regulatory T cells with superior antidiabetogenic properties than wild-type NOD mice. We propose that I-A(b), and possibly other protective MHC class II molecules, afford disease resistance by engaging a naturally occurring constellation of MHC-promiscuous autoreactive T-cell clonotypes, promoting their deviation into autoregulatory T cells.
authors: Department of Microbiology, Immunology and Infectious Diseases, Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine,  University of Calgary, Calgary, AB,  Canada T2N 4N1.
authors: Sue
authors: S
authors: Tsai
authors: Pau
authors: P
authors: Serra
authors: Xavier
authors: X
authors: Clemente-Casares
authors: Jun
authors: J
authors: Yamanouchi
authors: Shari
authors: S
authors: Thiessen
authors: Robyn M
authors: RM
authors: Slattery
authors: John F
authors: JF
authors: Elliott
authors: Pere
authors: P
authors: Santamaria
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D053547:Keratin-14 / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology; D019076:Transgenes / Q000235:genetics
chemical_list: D039521:CD11c Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D053547:Keratin-14
references: Immunity. 1995 Sep;3(3):273-82
references: 7552993
references: Nat Med. 2008 Nov;14(11):1227-35
references: 18953350
references: Science. 1990 Jul 20;249(4966):293-5
references: 2115690
references: Cell. 1996 May 3;85(3):291-7
references: 8616883
references: J Exp Med. 1997 Oct 6;186(7):1059-75
references: 9314555
references: J Immunol. 1996 Nov 15;157(10):4726-35
references: 8906855
references: Diabetes. 2002 Feb;51(2):325-38
references: 11812739
references: J Clin Invest. 2011 Jan;121(1):288-95
references: 21135507
references: Clin Immunol. 2004 Dec;113(3):318-25
references: 15507397
references: Nature. 2007 Dec 6;450(7171):887-92
references: 18004301
references: Cell. 1993 Sep 24;74(6):1089-100
references: 8402882
references: Diabetes Obes Metab. 2009 Feb;11 Suppl 1:31-45
references: 19143813
references: J Immunol. 2004 Jan 15;172(2):871-9
references: 14707058
references: J Immunol. 2002 Jan 1;168(1):87-94
references: 11751950
references: J Exp Med. 2004 Mar 1;199(5):725-30
references: 14993255
references: Nature. 1987 Oct 15-21;329(6140):599-604
references: 3309680
references: Nature. 1990 Jun 21;345(6277):724-6
references: 1972779
references: J Immunol. 1999 Apr 15;162(8):4627-36
references: 10202002
references: J Clin Invest. 2003 Sep;112(6):902-14
references: 12975475
references: Nat Rev Immunol. 2006 Apr;6(4):271-82
references: 16557259
references: Nat Rev Genet. 2005 Feb;6(2):109-18
references: 15716907
references: Annu Rev Immunol. 2012;30:95-114
references: 22149933
references: Curr Opin Immunol. 2009 Dec;21(6):590-5
references: 19699075
references: Eur J Immunol. 1993 Oct;23(10):2667-75
references: 8405065
references: J Exp Med. 1997 Nov 17;186(10):1663-76
references: 9362527
references: Nature. 1996 Sep 5;383(6595):81-5
references: 8779719
references: J Exp Med. 1998 Feb 2;187(3):379-87
references: 9449718
references: J Exp Med. 1996 Apr 1;183(4):1879-92
references: 8666944
references: J Immunol. 1986 Apr 15;136(8):2953-61
references: 2420879
references: Diabetes. 1997 Dec;46(12):1970-4
references: 9392482
references: Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9311-6
references: 10430939
references: J Exp Med. 1992 Jul 1;176(1):67-77
references: 1613467
references: Immunity. 2000 Jun;12(6):699-710
references: 10894169
references: Immunity. 2010 Apr 23;32(4):446-56
references: 20412755
references: J Immunol. 1998 Nov 1;161(9):4489-92
references: 9794372
references: Annu Rev Immunol. 2004;22:531-62
references: 15032588
references: Cell. 1996 May 3;85(3):311-8
references: 8616887
references: Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9566-70
references: 8415742