The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model.
MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic beta cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.
Wen
L
L
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. li.wen@yale.edu
Chen
N Y
NY
Tang
J
J
Sherwin
R
R
Wong
F S
FS
D000818:Animals; D001854:Bone Marrow Cells; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II; D015994:Incidence; D007328:Insulin / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D012793:Sialadenitis / Q000276:immunology; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D019076:Transgenes
D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015804:HLA-DR4 Antigen; D000949:Histocompatibility Antigens Class II; D007328:Insulin