Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes

Eur J Immunol. 2002 Mar;32(3):662-70. doi: 10.1002/1521-4141(200203)32:3<662::AID-IMMU662>3.0.CO;2-5.

Abstract

Immunodominant T cell epitopes from the autoantigen human cartilage glycoprotein 39 have previously been mapped in the context of HLA-DR*0401 and *0402, using mice expressing HLA-DR4 transgenes. We measured the dissociation rates of these epitopes from soluble recombinant DR*0401 and DR*0402 to assess the relationship between peptide/HLA-DR4 kinetic stability and immunogenicity. Experiments were performed at endosomal pH (5.5) and at cell surface pH (7), in the absence and presence of soluble recombinant HLA-DM (sDM). All (4/4) immunodominant peptide/HLA-DR complexes exhibit dissociation half-times of 1h to several days. In contrast, most (3/4) non-immunodominant complexes dissociate with half-times <30 min under at least one of these conditions. Interestingly, a complex which is stable except in the presence of HLA-DM at pH 5.5 is immunogenic only following peptide immunization, while a complex which is stable at acidic but not at neutral pH, is non-immunogenic following either whole protein or peptide immunization. These data indicate that kinetic stability of peptide/MHC complexes in vivo is a key determinant of immunogenicity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipokines
  • Amino Acid Sequence
  • Animals
  • Antigen Presentation / immunology*
  • Antigens / chemistry
  • Antigens / immunology*
  • Cell Membrane / immunology
  • Cells, Cultured
  • Chitinase-3-Like Protein 1
  • DNA, Complementary / genetics
  • Drosophila melanogaster / cytology
  • Endosomes / chemistry
  • Endosomes / immunology
  • Glycoproteins / chemistry
  • Glycoproteins / immunology*
  • HLA-D Antigens / immunology
  • HLA-DR4 Antigen / chemistry
  • HLA-DR4 Antigen / immunology*
  • Humans
  • Hybridomas / immunology
  • Hydrogen-Ion Concentration
  • Immunization
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / immunology*
  • Kinetics
  • Lectins
  • Macromolecular Substances
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / immunology
  • Structure-Activity Relationship
  • T-Lymphocytes / immunology

Substances

  • Adipokines
  • Antigens
  • CHI3L1 protein, human
  • Chitinase-3-Like Protein 1
  • DNA, Complementary
  • Glycoproteins
  • HLA-D Antigens
  • HLA-DM antigens
  • HLA-DR4 Antigen
  • Immunodominant Epitopes
  • Lectins
  • Macromolecular Substances
  • Peptide Fragments
  • Recombinant Fusion Proteins