title: EBV latent membrane proteins (LMPs) 1 and 2 as immunotherapeutic targets: LMP-specific CD4+ cytotoxic T cell recognition of EBV-transformed B cell lines.
abstract: The EBV-latent membrane proteins (LMPs) 1 and 2 are among only three viral proteins expressed in EBV-associated Hodgkin's lymphoma and nasopharyngeal carcinoma. Since these tumors are HLA class I and class II-positive, the LMPs could serve as both CD8+ and CD4+ T cell targets. In contrast to CD8 responses, very little is known about CD4 responses to LMPs. In this study, we describe CD4+ T cell clones defining four LMP1- and three LMP2-derived peptide epitopes and their restricting alleles. All clones produced Th1-like cytokines in response to peptide and most killed peptide-loaded target cells by perforin-mediated lysis. Although clones to different epitopes showed different functional avidities in peptide titration assays, avidity per se was a poor predictor of the ability to recognize naturally infected B lymphoblastoid cell lines (LCLs) expressing LMPs at physiologic levels. Some epitopes, particularly within LMP1, consistently mediated strong LCL recognition detectable in cytokine release, cytotoxicity, and outgrowth inhibition assays. Using cyclosporin A to selectively block cytokine release, we found that CD4+ T cell cytotoxicity is the key effector of LCL outgrowth control. We therefore infer that cytotoxic CD4+ T cells to a subset of LMP epitopes could have therapeutic potential against LMP-expressing tumors.
authors.affiliation: Cancer Research United Kingdom Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, United Kingdom.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Haigh
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Lin
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Hui
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
authors.forename: Graham S
authors.initials: GS
authors.lastname: Taylor
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000628:therapy; D006801:Humans; D015448:Leukemia, B-Cell / Q000628:therapy / Q000821:virology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000939:Epitopes; D010455:Peptides; D014763:Viral Matrix Proteins