NECROSIS AND APOPTOSIS ASSOCIATED WITH DISTINCT CA2-CELLS ATTACKED BYHUMAN NATURAL-KILLER-CELLS( RESPONSE PATTERNS IN TARGET)

1. During the process of cell death, rises in cytosolic Ca2+ concentra tion ([Ca2+](i)) together with co structural changes were investigated in target cells attacked by purified CD3(-),CD16(+) human natural kil ler (NK) cells. 2. In the target cell line K562, a rapid [Ca2+](i) ris e to 1-2 mu M occurred a few minutes after NK cell-target cell contact , immediately followed by leakage of the Ca2+ indicator dye fura-2 fro m the cell. Cells were permeabilized, but their chromatin was not frag mented. The changes were basically consistent with those seen in necro sis induced by activated complement. 3. In the target cell line MOLT-4 , which expressed the apoptosis-inducing surface antigen Fas much more strongly than K562, the majority of attacked cells displayed a [Ca2+] (i) rise to 0 . 7-1 mu M followed by a slow decline, often associated with diminishing [Ca2+](i) oscillations. As a whole, [Ca2+](i) remaine d higher than 150 nM for at least 1 . 5-3 h (similar to 100 nai in con trol cells). 4. MOLT-4 cells attacked by NK cells became bubble shaped within 20 min of the main [Ca2+](i) rise reaching its peak, and then both the cell and chromatin st-ere fragmented into small pieces. These findings were basically consistent with those in apoptosis induced by a monoclonal antibody against the surface antigen Fas. 5. NK cells in duced both necrosis and apoptosis in cell lines insensitive to NK cell s in the presence of an antibody against the major histocompatibility complex class I (antibody-dependent cell-mediated cytotoxicity, ADCC). The distinct Ca2+ response patterns described above corresponded to n ecrosis or apoptosis in different cells stimulated by the common ADCC pathway. 6. Human NW cells mere found to be capable of inducing necros is (membrane damage) or apoptosis (nuclear damage) depending on the ta rget cell types. The characteristic Ca2+ response profile was a good i ndicator for distinguishing between the modes of cell death induced by the cytotoxicity of the killer cells.