ABSTRACT
EBV transformation of human B cells in vitro results in establishment of immortalized cell lines (lymphoblastoid cell lines (LCL)) that express viral transformation-associated latent genes and exhibit a fixed, lymphoblastoid phenotype. In this report, we show that CD4(+) T cells can modify the differentiation state of EBV-transformed LCL. Coculture of LCL with EBV-specific CD4(+) T cells resulted in an altered phenotype, characterized by elevated CD38 expression and decreased proliferation rate. Relative to control LCL, the cocultured LCL were markedly less susceptible to lysis by EBV-specific CD8(+) CTL. In contrast, CD4(+) T cell-induced differentiation of LCL did not diminish sensitivity of LCL to lysis by CD8(+) CTL specific for an exogenously loaded peptide Ag or lysis by alloreactive CD8(+) CTL, suggesting that differentiation is not associated with intrinsic resistance to CD8(+) T cell cytotoxicity and that evasion of lysis is confined to EBV-specific CTL responses. CD4(+) T cell-induced differentiation of LCL and concomitant resistance of LCL to lysis by EBV-specific CD8(+) CTL were associated with reduced expression of viral latent genes. Finally, transwell cocultures, in which direct LCL-CD4(+) T cell contact was prevented, indicated a major role for CD4(+) T cell cytokines in the differentiation of LCL.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cell Line, Transformed/cytology , Cell Transformation, Viral/immunology , Cytotoxicity, Immunologic , Epitopes, T-Lymphocyte/immunology , Herpesvirus 4, Human/immunology , Lymphocyte Activation , T-Lymphocytes, Cytotoxic/immunology , Adult , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/virology , CD4-Positive T-Lymphocytes/virology , CD58 Antigens/biosynthesis , CD58 Antigens/physiology , Cell Adhesion Molecules/biosynthesis , Cell Communication/immunology , Cell Differentiation/immunology , Cell Line, Transformed/immunology , Cell Line, Transformed/metabolism , Cell Line, Transformed/virology , Coculture Techniques , Cytotoxicity Tests, Immunologic , Down-Regulation/genetics , Down-Regulation/immunology , HLA Antigens/biosynthesis , Herpesvirus 4, Human/genetics , Histocompatibility Antigens Class I/biosynthesis , Humans , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/biosynthesis , T-Lymphocytes, Cytotoxic/virology , Virus Latency/genetics , Virus Latency/immunologyABSTRACT
Identification of tumor-specific target antigens has been a major hurdle for the treatment of malignant disease by vaccination or immunotherapy. A second challenge has been the induction of therapeutically effective immune responses to these 'self' antigens. The recent recognition of dendritic cells as powerful antigen-presenting cells capable of inducing primary T-cell responses in vitro and in vivo--in combination with identification of tumor-specific antigens--has generated widespread interest in dendritic cell-based immunotherapy against a wide variety of tumors. In this review, a series of recently identified novel ovarian tumor antigens is discussed, and the potential for therapeutic dendritic cell vaccination targeted against these antigens is assessed.
