SUSCEPTIBILITY TO CYTOTOXIC T-LYMPHOCYTE-INDUCED APOPTOSIS IS A FUNCTION OF THE PROLIFERATIVE STATUS OF THE TARGET

Cytotoxic T lymphocytes (CTL) kill cells by perturbing the target's pl asma membrane and by inducing the disintegration df the target cell's DNA into oligonucleosomal fragments, a process characteristic of apopt osis. We show that the DNA fragmentation event is distinct from the me mbrane lysis event and is dependent on the state of target cell activa tion or commitment into the mitotic cycle. Quiescent cells were refrac tory to DNA fragmentation, but not to membrane lysis. Log phase growth , transformation with c-myc, or infection of quiescent G(0) targets wi th herpes simplex virus-1, which induces a competent state for DNA syn thesis, all enhanced target cell susceptibility to CTL-induced DNA fra gmentation without altering the membrane lysis. These results suggest that G(0) cells are resistant to CTL-induced apoptosis, but that entry into G(1) or a G(1)-like state by growth factors, cellular transforma tion, or DNA virus infection renders them competent to enter the apopt otic pathway(s).