title: Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules.
abstract: Major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL) recognize peptide epitopes of protein antigens in a hierarchical fashion. We investigated whether proteolytic cleavage, in particular by proteasomes, is important in determining epitope hierarchy. Using highly purified 20S proteasomes, we find preferred cleavage sites directly adjacent to the N- and C-terminal ends of the immunodominant epitope of chicken ovalbumin, Ova257-264, while most of the subdominant epitope, Ova55-62, is destroyed by a major cleavage site located within this epitope. Moreover, we show that variations in amino acid sequences flanking these epitopes influence proteasomal cleavage patterns in parallel with the efficacy of their presentation. The results suggest that proteasomal cleavage within and adjacent to class I-restricted epitopes contributes to their level of presentation.
authors.affiliation: Max Planck Institut für Immunbiologie, Freiburg, Federal Republic of Germany.
authors.forename: G
authors.initials: G
authors.lastname: Niedermann
authors.forename: S
authors.initials: S
authors.lastname: Butz
authors.forename: H G
authors.initials: HG
authors.lastname: Ihlenfeldt
authors.forename: R
authors.initials: R
authors.lastname: Grimm
authors.forename: M
authors.initials: M
authors.lastname: Lucchiari
authors.forename: H
authors.initials: H
authors.lastname: Hoschützky
authors.forename: G
authors.initials: G
authors.lastname: Jung
authors.forename: B
authors.initials: B
authors.lastname: Maier
authors.forename: K
authors.initials: K
authors.lastname: Eichmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism*; D006183:H-2 Antigens / Q000235:genetics; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex
chemical_list: D000939:Epitopes; D006183:H-2 Antigens; D016056:Immunodominant Epitopes; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D010047:Ovalbumin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex