title: Efficient killing of chronic B-lymphocytic leukemia cells by superantigen-directed T cells.
abstract: In vitro studies have indicated that chronic lymphocytic leukemia of B-cell origin (B-CLL) is resistant to cytotoxic effector lymphocytes such as natural killer and lymphokine activated killer (LAK) cells. We show here that B-cell cells are sensitive to Staphylococcal enterotoxin (SE) A-directed T-cell killing. Activation of the target cells by phorbol ester (tetradecanoyl phorbol acetate, [TPA]) greatly enhances their sensitivity to lysis. In SE-dependent cellular cytotoxicity (SDCC), members of the SE superantigen family form a bridge between T cells and target cells expressing major histocompatability complex class II molecules. Binding of SEA to the T-cell-receptor V beta region induces a strong cytotoxic capacity and cytokine production. Cells from 9 B-CLL patients were cultured in the presence or absence of TPA and used as targets in a 4-hour SDCC assay using an allogeneic T-cell line as effector. At an effector:target cell ratio 30:1, 70% to 80% of TPA-induced B-CLL cells were killed. Even at the effector:target ratio of 3:1, 47% +/- 6% of TPA-activated B-cell cells were lysed compared with 13% +/- 2% of resting cells (P < .001). A T-cell line established from a B-CLL patient killed autologous tumor cells as efficiently as allogeneic effectors. SEA-directed T cells were far more lytic to B-CLL cells compared with LAK cells or lectin (phytohemagglutinin-directed T cells. Mechanisms of SDCC lysis were investigated. Effector plus target cell supernatants contained high levels of tumor necrosis factor (TNF)-alpha and interferon-gamma, but these supernatants were not directly toxic to B-CLL cells in short term culture. High concentrations of recombinant TNF-alpha or TNF-beta had no lytic effect. Addition of neutralizing anti-TNF-alpha and anti-TNF-beta antibodies into the SDCC assay did not inhibit SEA-directed T-cell killing. TPA-activated B-CLL cells showed a 1.2- to 13-fold increased expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen (LFA)-1, and LFA-3, whereas expression of HLA class II molecules increased up to 5 times. The expression of CD72, CD40, and BB-1/B7 increased 1.8 to 4.5 times. The role of these surface molecules in SDCC was analyzed in blocking experiments with monoclonal antibodies. Antibodies to ICAM-1, CD18, and HLA-DR abolished the cytotoxicity, and a substantial reduction was seen with antibody to CD72.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Wallgren
authors.forename: R
authors.initials: R
authors.lastname: Festin
authors.forename: C
authors.initials: C
authors.lastname: Gidlöf
authors.forename: M
authors.initials: M
authors.lastname: Dohlsten
authors.forename: T
authors.initials: T
authors.lastname: Kalland
authors.forename: T H
authors.initials: TH
authors.lastname: Tötterman
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000276:immunology*; D006684:HLA-DR Antigens / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D013211:Staphylococcus aureus; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D018821:CD18 Antigens; C064228:CD72 protein, human; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004768:Enterotoxins; D006684:HLA-DR Antigens; D018799:Intercellular Adhesion Molecule-1; C026066:enterotoxin A, Staphylococcal; D013755:Tetradecanoylphorbol Acetate