Natural killer cell activation-associated induction of target cell DNA fragmentation in a spontaneously regressing rat histiocytoma.

The spontaneous regression of AK-5 histiocytoma is mediated by natural killer (NK) cells through antibody-dependent cell-mediated cellular cytotoxicity (ADCC) and the target cell death involves necrosis and apoptosis. We have studied the NK cell activation and the associated induction of apoptosis in the AK-5 tumour in rats. NK cells from immune animals expressed very low levels of CD16 and CD25 surface receptors, as revealed by Northern hybridization and flow cytometry. Interaction between NK cells and antibody-tagged AK-5 cells triggered the expression of these receptors to a higher level and affected AK-5 killing. Treatment of naive NK cells in vitro with interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and IL-12 also enhanced the expression of these activation markers. Co-culture of NK cells from immune animals with antibody-tagged AK-5 cells induced formation of nuclear bodies in AK-5 and extensive fragmentation of AK-5 cell DNA. NK-mediated apoptosis was inhibited by zinc, actinomycin D and cycloheximide. The in vitro treatment of NK cells with cytokines enhanced their ability to induce apoptosis in AK-5 tumour. These results suggest that the NK cells acquire their ability to induce apoptosis in AK-5 tumour in association with their optimal activation.