Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients

• Published in: The Journal of clinical investigation Vol. 99; no. 10; pp. 2405 - 2415
• Main Authors: Endl, J, Otto, H, Jung, G, Dreisbusch, B, Donie, F, Stahl, P, Elbracht, R, Schmitz, G, Meinl, E, Hummel, M, Ziegler, A G, Wank, R, Schendel, D J
• Format: Journal Article
• Language: English
• Published: United States 15.05.1997
• Subjects: Alleles; Amino Acid Sequence; Antibodies, Monoclonal; Antigen-Presenting Cells - immunology; Cell Line; Cells, Cultured; Cerebellum - enzymology; Diabetes Mellitus, Type 1 - immunology; Epitopes - analysis; Epitopes - chemistry; Glutamate Decarboxylase - chemistry; Glutamate Decarboxylase - immunology; Haplotypes; HLA-DR Antigens - genetics; Humans; Interferon-gamma - biosynthesis; Interleukin-2 - biosynthesis; Interleukin-4 - biosynthesis; Interleukin-6 - biosynthesis; Lymphocyte Activation; Male; Molecular Sequence Data; T-Lymphocytes - immunology
• ISSN: 0021-9738
• DOI: 10.1172/JCI119423

Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.