TARGET-EFFECTOR CELL-INTERACTION IN THE NATURAL-KILLER CELL SYSTEM .5. ENERGY-REQUIREMENTS, MEMBRANE INTEGRITY, AND THE POSSIBLE INVOLVEMENT OF LYSOSOMAL-ENZYMES

Abstract

Various inhibitors were used to study the mechanism of natural killing (NK) [by mouse cells] and to compare it to lympholysis by cytotoxic T [thymus-derived] lymphocytes (CTL). The respiratory inhibitors DNP [dinitrophenol] and NaN3 or low temperature (O.degree. C) blocked the cell contact phase of target-effector interaction in the CTL system but not the NK system. The lytic stage was also inhibited by the glycolytic inhibitors, iodoacetate and NaF, in the NK system as previously shown in the CTL system. Dimethylsulfoxide, a dipolar solvent, and cytochalasin B, a microtubule disruptor, inhibited NK target binding. Pretreatment of NK cells with glutaraldehyde, a protein cross-linking agent, completely prevented lysis, but not the formation of target-effector conjugates. The lytic phase of NK lysis was inhibited by chloroquine which also inhibited lysosomal enzyme function. Lysosome defective, beige mutant mice were also totally deficient in NK lytic function and this defect could not be restored with c[cyclic]GMP. T cell and macrophage mediated cytolysis is relatively normal in beige mice. The mechanism of NK cytolysis is apparently a complex, multistep process which is fundamentally different from that occurring in CTL. A stimulus-secretion model of NK cytolysis is presented in which it is postulated that lysosomal enzymes may be the lytic molecules.