HLA-DQ8-associated T cell responses to the diabetes autoantigen phogrin (IA-2 beta) in human prediabetes.
Susceptibility to type 1A autoimmune diabetes is linked to expression of particular MHC class II molecules, notably HLA-DQ8 in man and the orthologous I-Ag7 in the nonobese diabetic mouse. In the present study, we analyzed two peptide epitopes (peptides 2 and 7) from the diabetes autoantigen phogrin (IA-2beta), in the context of their presentation by the I-Ag7 and HLA-DQ8 molecules and their role as potential T cell antigenic epitopes in human diabetes. Both of these peptides are targets of diabetogenic CD4+ T cell clones in the nonobese diabetic mouse. Transgenic mice expressing HLA-DQ8 as the sole class II molecule generated a robust T cell-proliferative response when primed with peptide 2 or peptide 7 in CFA. Analysis of the IL-2 secretion from peptide 2-reactive T cell hybridomas stimulated with alanine-substituted peptides identified three residues that were crucial to the response. Among 41 islet cell Ag-positive prediabetic human subjects, 36.5% showed PBMC-proliferative responses to peptide 7, 17.1% to peptide 2, and 17.1% to both peptides; no response was seen among 20 matched healthy controls. Stratification of the data based upon HLA haplotype suggested that peptide 7 could be presented by at least one HLA-DR molecule in addition to HLA-DQ8, a finding that was supported by blocking studies with monomorphic mAbs. The results indicate that common phogrin peptides are targeted by autoreactive T cells in human and murine type 1A diabetes, and that the responses may in part be associated with the similar peptide-binding specificities of I-Ag7 and HLA-DQ8.
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B-140, Denver, CO 80262, USA.
Katalin
K
Kelemen
Peter A
PA
Gottlieb
Amy L
AL
Putnam
Howard W
HW
Davidson
Dale R
DR
Wegmann
John C
JC
Hutton
D000293:Adolescent; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D007376:Interleukin-2 / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000008:administration & dosage / Q000276:immunology*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; C096322:ICA512 autoantibody; D007376:Interleukin-2; D008565:Membrane Proteins; D010446:Peptide Fragments; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8