Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes-associated human MHC class II allele, DRB1*0401

J Clin Invest. 1996 Dec 1;98(11):2597-603. doi: 10.1172/JCI119079.

Abstract

The identification of class II binding peptide epitopes from autoimmune disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of type 1 diabetes, T cell and B cell reactivity to the autoantigen glutamic acid decarboxylase 65 (GAD65) is associated with disease development in humans and in nonobese diabetic (NOD) mice. In this study, we identify two DRB1*0401-restricted T cell epitopes from human GAD65, 274-286, and 115-127. Both peptides are immunogenic in transgenic mice expressing functional DRB1*0401 MHC class II molecules but not in nontransgenic littermates. Processing of GAD65 by antigen presenting cells (APC) resulted in the formation of DRB1*0401 complexes loaded with either the 274-286 or 115-127 epitopes, suggesting that these naturally derived epitopes may be displayed on APC recruited into pancreatic islets. The presentation of these two T cell epitopes in the islets of DRB1*0401 individuals who are at risk for type 1 diabetes may allow for antigen-specific recruitment of regulatory cells to the islets following peptide immunization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Animals
  • Autoantibodies / analysis*
  • B-Lymphocytes / immunology
  • Cell Line
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes / analysis*
  • Epitopes / chemistry
  • Genes, MHC Class II
  • Glutamate Decarboxylase / biosynthesis
  • Glutamate Decarboxylase / immunology*
  • HLA-DR Antigens / biosynthesis
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / immunology
  • T-Lymphocytes / immunology*

Substances

  • Autoantibodies
  • Epitopes
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • Peptide Fragments
  • Recombinant Proteins
  • Glutamate Decarboxylase