Prediction of HLA-DQ8beta cell peptidome using a computational program and its relationship to autoreactive T cells.
The goal was to identify HLA-DQ8-bound beta cell epitopes important in the T cell response in autoimmune diabetes. We first identified HLA-DQ8 (DQA1*0301/DQB1*0302) beta cell epitopes using a computational approach and then related their identification to CD4 T cell responses. The computational program (TEA-DQ8) was adapted from one previously developed for identifying peptides bound to the I-A(g7) molecule and based on a library of naturally processed peptides bound to HLA-DQ8 molecules of antigen-presenting cells. We then examined experimentally the response of NOD.DQ8 mice immunized with peptides derived from the Zinc transporter 8 protein. Log-of-odds scores on peptides were experimentally validated as an indicator of peptide binding to HLA-DQ8 molecules. We also examined previously published data on diabetic autoantigens, including glutamic acid decarboxylase-65, insulin and insulinoma-associated antigen-2, all tested in NOD.DQ8 transgenic mice. In all examples, many peptides identified with a favorable binding motif generated an autoimmune T cell response, but importantly many did not. Moreover, some peptides with weak-binding motifs were immunogenic. These results indicate the benefits and limitations in predicting autoimmune T cell responses strictly from MHC-binding data. TEA-DQ8 performed significantly better than other prediction programs.
Chang
Kuan Y
KY
Division of Immunology, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Unanue
Emil R
ER
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D027682:Cation Transport Proteins / Q000276:immunology; D019295:Computational Biology; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology / Q000378:metabolism*; D007114:Immunization; D007328:Insulin / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D000075703:Zinc Transporter 8
D001324:Autoantigens; D027682:Cation Transport Proteins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D007328:Insulin; D010455:Peptides; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2