title: The lifespan of major histocompatibility complex class I/peptide complexes determines the efficiency of cytotoxic T-lymphocyte responses.
abstract: Major histocompatibility complex (MHC)/peptide association and stability are determined by specific amino acid interactions between peptide antigens and the MHC groove, and are regarded as a critical feature in ensuring efficient monitoring by T cells. In this investigation we examined the relationship between MHC/peptide stability and the immunostimulatory capacity of MHC/peptide complexes. For this purpose we compared synthetic peptide analogues derived from the immunodominant HLA-A11-presented IVTDFSVIK (IVT) epitope, for their capacity to reactivate IVT-specific memory cytotoxic T-lymphocyte (CTL) responses. The analogues differentiated from the wild-type epitope by single amino acid substitution at position 2. All peptides showed similar affinity for HLA-A11 molecules and were recognized by IVT-specific CTL clones, but induced HLA-A11 complexes at the cell surface with different lifespan. This model offered the possibility of comparing the capacity of an immunogenic epitope to stimulate a unique population of T-cell precursors depending on the lifespan of its presentation at the cell surface. We demonstrated that stable HLA-A11/peptide complexes efficiently stimulate IVT-specific CTL responses, while HLA-A11/peptide complexes with short lifespan do not. The precise identification of the role of amino acid residues in the formation of stable MHC/peptide complexes may be relevant for the design of wild-type-derived epitopes with high immunogenicity. These analogues may have important applications in the immunotherapy of infectious diseases and immunogenic tumours.
authors.affiliation: Biochemistry and Molecular Biology, University of Ferrara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Micheletti
authors.forename: M
authors.initials: M
authors.lastname: Bazzaro
authors.forename: A
authors.initials: A
authors.lastname: Canella
authors.forename: M
authors.initials: M
authors.lastname: Marastoni
authors.forename: S
authors.initials: S
authors.lastname: Traniello
authors.forename: R
authors.initials: R
authors.lastname: Gavioli
mesh_terms: D018929:Cell Culture Techniques; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D059870:HLA-A11 Antigen; D006207:Half-Life; D004854:Herpesvirus 4, Human / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments