Sr++-induced inhibition of human natural killer (NK) cell-mediated cytotoxicity

The cell believed to be responsible for human spontaneous cytotoxicity or natural killing (NK) has been described recently as a large granular lymphocyte (LGL). Because the intracytoplasmic granules of LGL appear to be peculiar to the subpopulation of mononuclear cells containing NK effectors, we have investigated their possible requirement in the cytolytic process. Experiments reported here show that Sr++, a cation known to cause degranulation of granulocytes, caused a dose- and time-dependent inhibition of the NK activity of human peripheral blood mononuclear cells. A single-cell NK assay showed that the number of cytotoxic cells was not significantly reduced, but that Sr++ inhibited NK by preventing individual effector cells from engaging in multiple lethal hits. Moreover, the inhibition of NK appeared to be reversible; culture in vitro of Sr++-treated PBMC resulted in the eventual return of cytolytic activity in these cells. Augmentation of NK by interferon (IFN) was similarly blocked by Sr++. In addition, Sr++ also inhibited the NK activity of IFN-prestimulated effector cells and, as before, NK function returned during subsequent culture. These results indicated that the return of NK function after Sr++ treatment was the result of reactivation of cytotoxic cells rather than recruitment of new effectors. We have shown in other studies that Sr++ degranulates LGL, and the data presented here provide support for the hypothesis that the intracytoplasmic granules of LGL are required for NK-mediated cytotoxicity.