CYTOKINE-ENHANCED NK CELL-MEDIATED CYTOTOXICITY - POSITIVE MODULATORYEFFECTS OF IL-2 AND IL-12 ON STIMULUS-DEPENDENT GRANULE EXOCYTOSIS

NK cells are a subpopulation of lymphocytes that kill virally infected cells and tumor cells without previous sensitization. Although exposu re to distinct cytokines, including IL-2 and IL-12, can enhance these cytotoxic responses, the mechanism of this lymphokine-augmented killin g remains unclear. Inasmuch as the cytotoxic event is a multistep proc ess, there are many potential targets for lymphokine regulation. We fo cused on whether selected lymphokines directly modulate the intracellu lar signaling pathways critical for NK cell secretory function. In our experimental model, homogeneous, cloned human CD16(+)/CD3(-) NK cells were pretreated with either IL-2 or IL-12 and then stimulated with di rect pharmacologic activators of the secretory response (e.g., PMA and ionomycin for intact cells or GTP gamma S for streptolysin-O permeabi lized cells). Previous exposure of the cells to IL-2 or IL-12 enhanced the stimulus-induced release of granule-derived proteins (hexosaminid ase and serine proteases) in a cytokine concentration- and time-depend ent fashion. Furthermore, the cytokines increased the efficacies witho ut changing the potencies of the secretagogues used in these studies. These results suggest that IL-2 and IL-12 augment NK cell-mediated cyt otoxicity by increasing the maximal level of granule exocytosis evoked by Ca2+ and/or G protein-dependent intracellular signaling pathways.