title: CD8+ T cell responses to lytic EBV infection: late antigen specificities as subdominant components of the total response.
abstract: EBV elicits primary CD8(+) T cell responses that, by T cell cloning from infectious mononucleosis (IM) patients, appear skewed toward immediate early (IE) and some early (E) lytic cycle proteins, with late (L) proteins rarely targeted. However, L Ag-specific responses have been detected regularly in polyclonal T cell cultures from long-term virus carriers. To resolve this apparent difference between responses to primary and persistent infection, 13 long-term carriers were screened in ex vivo IFN-γ ELISPOT assays using peptides spanning the two IE, six representative E, and seven representative L proteins. This revealed memory CD8 responses to 44 new lytic cycle epitopes that straddle all three protein classes but, in terms of both frequency and size, maintain the IE > E > L hierarchy of immunodominance. Having identified the HLA restriction of 10 (including 7 L) new epitopes using memory CD8(+) T cell clones, we looked in HLA-matched IM patients and found such reactivities but typically at low levels, explaining why they had gone undetected in the original IM clonal screens. Wherever tested, all CD8(+) T cell clones against these novel lytic cycle epitopes recognized lytically infected cells naturally expressing their target Ag. Surprisingly, however, clones against the most frequently recognized L Ag, the BNRF1 tegument protein, also recognized latently infected, growth-transformed cells. We infer that BNRF1 is also a latent Ag that could be targeted in T cell therapy of EBV-driven B-lymphoproliferative disease.
authors.affiliation: School of Cancer Sciences and Medical Research Council Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Rachel J M
authors.initials: RJ
authors.lastname: Abbott
authors.forename: Laura L
authors.initials: LL
authors.lastname: Quinn
authors.forename: Alison M
authors.initials: AM
authors.lastname: Leese
authors.forename: Harry M
authors.initials: HM
authors.lastname: Scholes
authors.forename: Annette
authors.initials: A
authors.lastname: Pachnio
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D058501:Enzyme-Linked Immunospot Assay; D006680:HLA Antigens / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism; D007244:Infectious Mononucleosis / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism; D017735:Virus Latency / Q000276:immunology
chemical_list: D006680:HLA Antigens; D016056:Immunodominant Epitopes; C062724:P140 protein, Epstein-barr virus; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; D007371:Interferon-gamma