Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes.
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.
Hall
Frances C
FC
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Rabinowitz
Joshua D
JD
Busch
Robert
R
Visconti
Kevin C
KC
Belmares
Michael
M
Patil
Namrata S
NS
Cope
Andrew P
AP
Patel
Salil
S
McConnell
Harden M
HM
Mellins
Elizabeth D
ED
Sonderstrup
Grete
G
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
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