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

J Clin Invest. 1997 May 15;99(10):2405-15. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • HLA-DR Antigens / genetics*
  • Haplotypes
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / biosynthesis
  • Interleukin-4 / biosynthesis
  • Interleukin-6 / biosynthesis
  • Lymphocyte Activation
  • Male
  • Molecular Sequence Data
  • T-Lymphocytes / immunology*


  • Antibodies, Monoclonal
  • Epitopes
  • HLA-DR Antigens
  • Interleukin-2
  • Interleukin-6
  • Interleukin-4
  • Interferon-gamma
  • Glutamate Decarboxylase