title: Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells.
abstract: Cytokine-induced killer (CIK) cells are non-major histocompatibility complex-restricted cytotoxic cells generated by incubation of peripheral blood lymphocytes with anti-CD3 monoclonal antibody (MoAb), interleukin-2 (IL-2), IL-1, and interferon-gamma. Cells with the greatest effector function in CIK cultures coexpress CD3 and CD56 surface molecules. CIK cell cytotoxicity can be blocked by MoAbs directed against the cell surface protein leukocyte function associated antigen-1 but not by anti-CD3 MoAbs. CIK cells undergo release of cytoplasmic cytotoxic granule contents to the extracellular space upon stimulation with anti-CD3 MoAbs or susceptible target cells. Maximal granule release was observed from the CD3+ CD56+ subset of effector cells. The cytoplasmic granule contents are lytic to target cells. Treatment of the effector cells with a cell-permeable analog of cyclic adenosine monophosphate (cAMP) inhibited anti-CD3 MoAb and target cell-induced degranulation and cytotoxicity of CIK cells. The immunosuppressive drugs cyclosporin (CsA) and FK506 inhibited anti-CD3-mediated degranulation, but did not affect cytotoxicity of CIK cells against tumor target cells. In addition, degranulation induced by target cells was unaffected by CsA and FK506. Our results indicate that two mechanisms of cytoplasmic granule release are operative in the CD3+ CD56+ killer cells; however, cytotoxicity proceeds through a cAMP-sensitive, CsA- and FK506-insensitive pathway triggered by yet-to-be-identified target cell surface molecules.
authors.affiliation: Department of Medicine, Stanford University Medical Center, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Mehta
authors.forename: I G
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: I L
authors.initials: IL
authors.lastname: Weissman
authors.forename: R S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D015415:Biomarkers; D003994:Bucladesine / Q000494:pharmacology; D017252:CD3 Complex / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005089:Exocytosis; D053804:Granzymes; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016131:Lymphocyte Subsets / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000473:pathology; D016853:Muromonab-CD3 / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D015415:Biomarkers; D017252:CD3 Complex; D019002:CD56 Antigen; D016207:Cytokines; D016853:Muromonab-CD3; D009363:Neoplasm Proteins; D003994:Bucladesine; D016572:Cyclosporine; D000242:Cyclic AMP; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; D016559:Tacrolimus