title: Recognition of homo- and heterosubtypic variants of influenza A viruses by human CD8+ T lymphocytes.
abstract: In the present study, the recognition of epitope variants of influenza A viruses by human CTL was investigated. To this end, human CD8(+) CTL clones, specific for natural variants of the HLA-B*3501-restricted epitope in the nucleoprotein (NP(418-426)), were generated. As determined in (51)Cr release assays and by flow cytometry with HLA-B*3501-peptide tetrameric complexes, CTL clones were found to be specific for epitopes within one subtype or cross-reactive with heterosubtypic variants of the epitope. Using eight natural variants of the epitope, positions in the 9-mer important for T cell recognition and involved in escape from CTL immunity were identified and visualized using multidimensional scaling. It was shown that positions 4 and 5 in the 9-mer epitope were important determinants of T cell specificity. The in vivo existence of CD8(+) cells cross-reactive with homo- and heterosubtypic variants of the epitope was further confirmed using polyclonal T cell populations obtained after stimulation of PBMC with different influenza A viruses. Based on the observed recognition patterns of the clonal and polyclonal T cell populations and serology, it is hypothesized that consecutive infections with influenza viruses containing different variants of the epitope select for cross-reactive T cells in vivo.
authors.affiliation: Department of Virology and WHO National Influenza Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Adrianus C M
authors.initials: AC
authors.lastname: Boon
authors.forename: Gerrie
authors.initials: G
authors.lastname: de Mutsert
authors.forename: Debbie
authors.initials: D
authors.lastname: van Baarle
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Alan S
authors.initials: AS
authors.lastname: Lapedes
authors.forename: Ron A M
authors.initials: RA
authors.lastname: Fouchier
authors.forename: Kees
authors.initials: K
authors.lastname: Sintnicolaas
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
mesh_terms: D000328:Adult; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002461:Cell Line, Transformed; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015797:HLA-B35 Antigen / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000145:classification / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology / Q000821:virology; D008875:Middle Aged; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D012703:Serotyping; D013194:Staining and Labeling; D014758:Viral Core Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015797:HLA-B35 Antigen; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D010446:Peptide Fragments; D014758:Viral Core Proteins