DIFFERENTIAL SENSITIVITY OF RESTING AND IL-2 ACTIVATED NK CELLS TO R-VERAPAMIL

Natural killer (NK) cells are the first lymphoid population to reconst itute the peripheral blood compartment of immunologically compromised bone marrow transplant (BMT) recipients. Recent data suggest that, amo ng patients transplanted for leukemia, NK cells can prevent or delay d isease relapse by mediating a cytotoxic graft vs leukemia (GvL) respon se. Although the major mechanism by which NK cells mediate target cell lysis involves degranulation and release of cytolytic effector molecu les (granzymes, proteoglycans, perforin), accumulating evidence sugges ts that NK cells possess additional pathways to mediate target cell ki lling. In fact, it is well recognized that recombinant cytokines such as IL-2 enhance the in vitro cytolytic activity of NK cells. In this s tudy, we observed that the lytic activity mediated by resting and IL-2 activated NK cells against the same target cell appears to occur via two distinct pathways, as distinguished by their differential response to R-verapamil. Specifically, we observed that 25 mu M R-verapamil in hibited the lytic activity of resting NK cells against K562 targets by approximately 50%. However, the lytic activity of IL-2 activated NK c ells was unaffected by this concentration of R-verapamil. Additional s tudies suggested that the inhibitory effect of R-verapamil on NK cytot oxic activity was associated with its ability to prevent degranulation of cytotoxic granules. Specifically, R-verapamil inhibited BLT estera se release from resting but not IL-2 activated NK cells. These data su ggest that IL-2 activated NK cells can promote target cell lysis by a pathway (possibly degranulation independent) distinct from that used b y resting NK cells. We speculate that the target of R-verapamil on res ting Mt cells is P-glycoprotein (Pgp), an ABC transporter that we rece ntly reported was expressed on NK cells and whose functional activity is known to be inhibited by R-verapamil.