title: The model B6(dom1) minor histocompatibility antigen is encoded by a mouse homolog of the yeast STT3 gene.
abstract: The B6(dom1) minor histocompatibility antigen (MiHA) is a model antigen, since it is both the epitome of an immunodominant epitope and an ideal target for adoptive cancer immunotherapy. Based on DNA sequencing and MS/MS analyses, we report that B6(dom1) corresponds to amino acids 770-778 (KAPDNRETL) of a protein we propose to call SIMP (source of immunodominant MHC-associated peptides) that is encoded by a mouse homolog of the yeast STT3gene. STT3, a member of the oligosaccharyltransferase complex, is essential for cell proliferation. Phenotypic and genotypic analyses among eight strains of mice revealed a precise correlation between susceptibility or resistance to B6(dom1)-specific cytotoxic T lymphocytes (CTLs) and the presence of a Glu vs Asp amino acid at position 776 of the SIMP protein, respectively. Strikingly, while the difference in the amino acid sequence 770-778 encoded by the two SIMP alleles represents a very conservative substitution, these allelic peptides were not crossreactive at the CTL level, and both peptides were immunodominant when presented to mice homozygous for the opposite allele. In addition, we have cloned a human ortholog of SIMP whose predicted protein shares 97% amino acid identity with mouse SIMP. These results strengthen the concept that MHC class-I-associated MiHAs originate as a consequence of rare polymorphisms among highly conserved genes. Furthermore, the notion that a peptide differing from a self analog by a single methylene group can be immunodominant has implications regarding our understanding of the mechanisms of immunodominance.
authors.affiliation: Department of Molecular Biology, Compatigene Inc., Montreal, Quebec, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: McBride
authors.forename: Chantal
authors.initials: C
authors.lastname: Baron
authors.forename: Serge
authors.initials: S
authors.lastname: Picard
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Martin
authors.forename: Daniel
authors.initials: D
authors.lastname: Boismenu
authors.forename: Alex
authors.initials: A
authors.lastname: Bell
authors.forename: John
authors.initials: J
authors.lastname: Bergeron
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D003601:Cytotoxicity Tests, Immunologic; D005800:Genes, Fungal; D016695:Glycosyltransferases / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006602:Hexosyltransferases; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics* / Q000276:immunology; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015003:Yeasts / Q000235:genetics
chemical_list: D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments; C469940:SIMP protein (770-778); D029701:Saccharomyces cerevisiae Proteins; D016695:Glycosyltransferases; D006602:Hexosyltransferases; C096554:STT3 protein, S cerevisiae; C551978:STT3B protein, human; C000629827:Stt3b protein, mouse