Molecular Mechanisms of Lymphocyte Cytotoxicity

Abstract

Natural killer (NK) cells are CD3−, T-cell receptor (TCR)−, large granular lymphocytes (LGL) that express spontaneous lytic activity against tumor cells, virally infected cells, and perhaps certain hematopoietic progenitor cells (Trinchieri, 1989). Understanding the cellular and molecular mechanisms by which NK cells recognize and destroy target cells has become an area of considerable interest. Previous studies (Henney, 1973; Herberman et al., 1986) with NK cells have proposed to divide the process of NK killing into four identifiable stages, consisting of: (1) target cell binding (adhesion), (2) effector cell activation (recognition/ signal transduction), (3) delivery of the lethal signal to the target (lethal hit), and (4) effector cell detachment and recycling. Ca2+ plays a central role in the killing process, yet only recently has it been possible to delineate more clearly the site(s) of Ca2+ requirements in the lytic mechanism. Early studies involving cytotoxic T lymphocyte (CTL) models and more recent studies with NK cells demonstrated that Ca2+ was required at a point in the lytic process distal to Mg2+-dependent target cell adhesion but proximal to target cell disintegration (Roder and Haliotis, 1980; Quan et al., 1982; Martz et al., 1983; Berke, 1989). Recent evidence supported a role for Ca2+ in the activation of a stimulus-secretion response by killer cells. It also suggested that Ca2+ can be a potent toxic agent if allowed to accumulate at high concentrations in target cells. Therefore, Ca2+ appears to be required not only to activate killer cell function but must also enter the killer cell to activate additional processes related to stimulus-secretion coupling. Analysis of the lethal hit by which killer lymphocytes mediate target cell damage has focused on CTL and their interactions with specific target cells (Roder and Haliotis, 1980; Quan et al., 1982). It suggested, but did not prove, that during “programming for lysis” the killer cells may deposit (or secrete) materials onto the target cell that mediate the lytic signals. The hypothesis that material(s) were transferred from a killer cell to a target cell was a requisite for this target cell lysis model (Henkart and Henkart, 1982). Collectively, numerous data support this hypothesis as a general phenomenon common to numerous types of killer cells. The observation that NK cells and in vitro- activated CTL contain intracytoplasmic azurophilic granules suggested that these granules may be released during the Ca2+-dependent stage of killing and may contain materials capable of mediating target cell lysis.KeywordsNatural Killer ActivityLarge Granular LymphocyteGranule ExocytosisTarget Cell LysisSerine EsteraseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.