title: Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA.
abstract: CMV and other viruses down-regulate the cell surface expression of class I HLA, and while this allows them to evade CTL, it may make infected cells more susceptible to lysis by NK cells, due to the failure to engage class I inhibitory receptors on the NK cell. We studied CMV infection and found that fibroblasts infected with virus strains Towne, Toledo, Davis, and C1FE were refractory to NK lysis, while those infected with strains AD169, C1F, or R7 were susceptible. All viral strains down-regulated class I HLA to a similar extent, and we concluded that there was no evidence for any correlation between the latter and susceptibility to NK lysis. In contrast, there was a strong correlation between NK killing of CMV-infected cells and cell surface levels of lymphocyte function-associated antigen-3 (LFA-3). Fibroblasts infected with the Towne, Toledo, Davis, and C1FE strains of CMV down-regulated LFA-3 expression and were refractory to lysis, while strains AD169, C1F, and R7 up-regulated LFA-3 and were susceptible to NK killing. U373 MG (malignant glioma) cells expressed constitutively high levels of LFA-3 and were sensitive to NK lysis when infected with any of the above-listed CMV strains. We estimated that a minimum of between 29,000 and 71,000 LFA-3 molecules per target cell were needed for NK susceptibility. The effects on LFA-3 expression were due to immediate early/early viral gene products. We also demonstrated that fibroblasts infected with the strains Towne, Toledo, Davis, and C1FE expressed a ganciclovir-sensitive late CMV gene product, which delivered an inhibitory signal to NK cells.
authors.affiliation: Department of Clinical Immunology, Royal Free Hospital School of Medicine, London, United Kingdom.
authors.forename: J M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: H G
authors.initials: HG
authors.lastname: Prentice
authors.forename: J E
authors.initials: JE
authors.lastname: Grundy
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018801:CD2 Antigens / Q000276:immunology; D018968:CD58 Antigens / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000145:classification / Q000187:drug effects / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000276:immunology*; D004730:Endothelium, Vascular; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000821:virology; D015774:Ganciclovir / Q000494:pharmacology; D006680:HLA Antigens / Q000096:biosynthesis / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate / Q000187:drug effects; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D008213:Lymphocyte Activation; D014407:Tumor Cells, Cultured
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D018968:CD58 Antigens; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D015774:Ganciclovir