title: Cytotoxic CD4+ T cell responses to EBV contrast with CD8 responses in breadth of lytic cycle antigen choice and in lytic cycle recognition.
abstract: EBV, a B lymphotropic herpesvirus, encodes two immediate early (IE)-, >30 early (E)-, and >30 late (L)-phase proteins during its replication (lytic) cycle. Despite this, lytic Ag-induced CD8 responses are strongly skewed toward IE and a few E proteins only, all expressed before HLA I presentation is blocked in lytically infected cells. For comparison, we examined CD4(+) T cell responses to eight IE, E, or L proteins, screening 14 virus-immune donors to overlapping peptide pools in IFN-γ ELISPOT assays, and established CD4(+) T cell clones against 12 defined epitopes for target-recognition assays. We found that the lytic Ag-specific CD4(+) T cell response differs radically from its CD8 counterpart in that it is widely distributed across IE, E, and L Ag targets, often with multiple reactivities detectable per donor and with IE, E, or L epitope responses being numerically dominant, and that all CD4(+) T cell clones, whether IE, E, or L epitope-specific, show strong recognition of EBV-transformed B cell lines, despite the lines containing only a small fraction of lytically infected cells. Efficient recognition occurs because lytic Ags are released into the culture and are acquired and processed by neighboring latently infected cells. These findings suggested that lytic Ag-specific CD4 responses are driven by a different route of Ag display than drives CD8 responses and that such CD4 effectors could be therapeutically useful against EBV-driven lymphoproliferative disease lesions, which contain similarly small fractions of EBV-transformed cells entering the lytic cycle.
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: Heather M
authors.initials: HM
authors.lastname: Long
authors.forename: Alison M
authors.initials: AM
authors.lastname: Leese
authors.forename: Odette L
authors.initials: OL
authors.lastname: Chagoury
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Connerty
authors.forename: Jared
authors.initials: J
authors.lastname: Quarcoopome
authors.forename: Laura L
authors.initials: LL
authors.lastname: Quinn
authors.forename: Claire
authors.initials: C
authors.lastname: Shannon-Lowe
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
mesh_terms: D000956:Antigens, Viral / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods*; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D018984:Epitopes, T-Lymphocyte; C033305:Epstein-Barr virus early antigen; C083204:Epstein-Barr virus early antigen diffuse component; D017874:Immediate-Early Proteins; D010750:Phosphoproteins; C090236:SM protein, Human herpesvirus 4; D015534:Trans-Activators; D007371:Interferon-gamma