title: Activation of NK cell cytotoxicity.
abstract: Natural killer (NK) cells are innate effector lymphocytes necessary for defence against stressed, microbe-infected, or malignant cells. NK cells kill target cells by either of two major mechanisms that require direct contact between NK cells and target cells. In the first pathway, cytoplasmic granule toxins, predominantly a membrane-disrupting protein known as perforin, and a family of structurally related serine proteases (granzymes) with various substrate specificities, are secreted by exocytosis and together induce apoptosis of the target cell. The granule-exocytosis pathway potently activates cell-death mechanisms that operate through the activation of apoptotic cysteine proteases (caspases), but can also cause cell death in the absence of activated caspases. The second pathway involves the engagement of death receptors (e.g. Fas/CD95) on target cells by their cognate ligands (e.g. FasL) on NK cells, resulting in classical caspase-dependent apoptosis. The comparative role of these pathways in the pathophysiology of many diseases is being dissected by analyses of gene-targeted mice that lack these molecules, and humans who have genetic mutations affecting these pathways. We are also now learning that the effector function of NK cells is controlled by interactions involving specific NK cell receptors and their cognate ligands, either on target cells, or other cells of the immune system. This review will discuss the functional importance of NK cell cytotoxicity and the receptor/ligand interactions that control these processes.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, Vic. 8006, Australia. mark.smyth@petermac.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.forename: Janice M
authors.initials: JM
authors.lastname: Kelly
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: Shayna E A
authors.initials: SE
authors.lastname: Street
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Serani L H
authors.initials: SL
authors.lastname: van Dommelen
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D017209:Apoptosis; D016207:Cytokines / Q000276:immunology; D003594:Cytoplasmic Granules / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012697:Serine Endopeptidases / Q000172:deficiency / Q000502:physiology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C075005:GNLY protein, human; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D054353:Perforin; D012697:Serine Endopeptidases