Cytotoxic T lymphocytes (CTL) kill cells by perturbing the target's plasma membrane and by inducing the disintegration of the target cell's DNA into oligonucleosomal fragments, a process characteristic of apoptosis. We show that the DNA fragmentation event is distinct from the membrane lysis event and is dependent on the state of target cell activation or commitment into the mitotic cycle. Quiescent cells were refractory to DNA fragmentation, but not to membrane lysis. Log phase growth, transformation with c-myc, or infection of quiescent G0 targets with herpes simplex virus-1, which induces a competent state for DNA synthesis, all enhanced target cell susceptibility to CTL-induced DNA fragmentation without altering the membrane lysis. These results suggest that G0 cells are resistant to CTL-induced apoptosis, but that entry into G1 or a G1-like state by growth factors, cellular transformation, or DNA virus infection renders them competent to enter the apoptotic pathway(s).

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