Cytotoxicity of natural killer cells: correlation with emperipolesis and surface enzymes

Cell-mediated cytotoxicity involving natural killer cells requires contact between effector and target cells for effective cytolysis. Ultrastructural studies of biopsies of primary human malignant melanoma showed mononuclear leukocytes to be located in close proximity to tumor cells and, on occasion, within the confines of the melanoma cell itself. This phenomenon, called emperipolesis, was examined in vitro to determine whether the same population of cells that exhibits emperipolesis is responsible for cytotoxicity. Since natural killer cells have been identified morphologically and functionally as large granular lymphocytes with surface receptors for the Fc portion of immunoglobulin (FcR+ cells), lymphocytes were depleted of FcR+ cells, and their cytotoxicity and ability to emperipolese were measured. Both of these properties were markedly diminished (88 and 85 per cent, respectively). Systematic comparison of emperipolesis and cytotoxicity from donors known to exhibit either high or low lymphocyte cytotoxicity showed perfect concordance. Ultrastructural analysis of in vitro emperipolesis revealed the emperipolesing lymphocytes to be FcR+ cells establishing identity with the large granular cells known to mediate cytotoxicity. The morphologic marker found in both FcR+ cells, purified by rosetting techniques, and in emperipolesed lymphocytes consisted of cytoplasmic parallel tubular arrays. Further studies designed to elucidate a mechanism for cytotoxicity and emperipolesis implicated cell surface proteases as mediators of these activities. Competitive inhibition of surface proteases with artificial and natural inhibitors markedly reduced both cytotoxicity and emperipolesis. Therefore, it is likely that lymphocytes that are FcR+ participate in cell-medicated cytotoxicity through mechanisms involving cell contact and enzyme-initiated damage of target cells. Emperipolesis represents one type of effector-target cell contact leading to cytotoxicity.