CD4+ and CD8+ T-cell clones from congenital rubella syndrome patients with IDDM recognize overlapping GAD65 protein epitopes. Implications for HLA class I and II allelic linkage to disease susceptibility.
To fully characterize human glutamic acid decarboxylase (GAD)65 protein T-cell epitopes associated with insulin-dependent diabetes mellitus (IDDM), CTL clones specific to GAD65 protein antigens were isolated from two congenital rubella syndrome (CRS)-associated IDDM patients. Overlapping nonamer T-cell epitopes recognized by both CD4+ or CD8+ CTL clones within peptides GAD65(252-266) and GAD65(274-286) were identified as sequences bounded by GAD65(255-266) with 6/9 overlapping residues, and GAD65(276-285) with 8/9 overlapping residues, respectively, using two panels of overlapping peptide analogs in cytotoxicity assays. HLA restrictive elements of the T-cell clones were also identified using a panel of B cell lines with different HLA phenotypes as targets in cytotoxicity assays. The antigenic GAD65 peptides elicited cytotoxic responses of peptide-specific CD4+ T-cell clones in the context of HLA DRB1*0404. The CD8+ T-cell clone specific to GAD65(255-263) was found to be restricted by HLA A3 and A11. Similarly, the CD8+ T-cell clone specific to GAD65(277-285) killed peptide-sensitized target cells expressing HLA B35 and B15. The observed HLA restriction of these overlapping epitopes implies that a tandem of [DRB1*0404-A11(3)] and/or a tandem of [DRB1*0404-B35(15)] might predispose CRS patients to development of IDDM.
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Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Jonsen
L A
LA
Metzger
D L
DL
Tingle
A J
AJ
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D012410:Rubella Syndrome, Congenital / Q000150:complications* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic
D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D005968:Glutamate Decarboxylase