title: CD4+ T-cell clones recognizing human lymphoma-associated antigens: generation by in vitro stimulation with autologous Epstein-Barr virus-transformed B cells.
abstract: Epstein-Barr virus (EBV)-specific T-cell preparations, generated by stimulating immune donor lymphocytes with the autologous virus-transformed B-lymphoblastoid cell line (LCL) in vitro, can be used to target EBV-positive malignancies. Although these preparations are enriched for EBV antigen-specific CD8(+) T cells, most also contain a CD4(+) T-cell population whose specificity is unknown. Here, we show that, although CD4(+) T-cell clones derived from such cultures recognize HLA class II-matched LCLs but not mitogen-activated B lymphoblasts, many (1) do not map to any known EBV antigen, (2) can be raised from EBV-naive as well as EBV-immune persons, and (3) can recognize a broad range of human B lymphoma-derived cell lines irrespective of EBV genome status, providing those lines to express the relevant HLA class II-restricting allele. Importantly, such CD4(+) clones not only produce IFNgamma but are also cytotoxic and can control the outgrowth of HLA-matched lymphoma cells in cocultivation assays. We infer that such CD4(+) T cells recognize cellular antigens that are preferentially up-regulated in EBV-transformed but not mitogen-activated B lymphoblasts and that are also expressed in a range of B-cell malignancies. Such antigens are therefore of potential value as targets for CD4(+) T cell-based immunotherapy.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Vincent Drive, Birmingham, United Kingdom.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Long
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zuo
authors.forename: Alison M
authors.initials: AM
authors.lastname: Leese
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Gudgeon
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.forename: Graham S
authors.initials: GS
authors.lastname: Taylor
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008223:Lymphoma / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D019014:fas Receptor