title: Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes.
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.
authors.affiliation: Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Frances C
authors.initials: FC
authors.lastname: Hall
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Robert
authors.initials: R
authors.lastname: Busch
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Visconti
authors.forename: Michael
authors.initials: M
authors.lastname: Belmares
authors.forename: Namrata S
authors.initials: NS
authors.lastname: Patil
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cope
authors.forename: Salil
authors.initials: S
authors.lastname: Patel
authors.forename: Harden M
authors.initials: HM
authors.lastname: McConnell
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.forename: Grete
authors.initials: G
authors.lastname: Sonderstrup
mesh_terms: D054392:Adipokines; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1; D018076:DNA, Complementary / Q000235:genetics; D004331:Drosophila melanogaster / Q000166:cytology; D011992:Endosomes / Q000737:chemistry / Q000276:immunology; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D006863:Hydrogen-Ion Concentration; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007700:Kinetics; D037102:Lectins; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D054392:Adipokines; D000941:Antigens; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D018076:DNA, Complementary; D006023:Glycoproteins; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015804:HLA-DR4 Antigen; D016056:Immunodominant Epitopes; D037102:Lectins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins