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.
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.
Endl
J
J
Boehringer Mannheim Research Center, D-82377 Penzberg. josef_endl@bmg.corange.com
Otto
H
H
Jung
G
G
Dreisbusch
B
B
Donie
F
F
Stahl
P
P
Elbracht
R
R
Schmitz
G
G
Meinl
E
E
Hummel
M
M
Ziegler
A G
AG
Wank
R
R
Schendel
D J
DJ
D000483:Alleles; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D002531:Cerebellum / Q000201:enzymology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000032:analysis* / Q000737:chemistry; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D006684:HLA-DR Antigens; D007376:Interleukin-2; D015850:Interleukin-6; D015847:Interleukin-4; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase