TARGET-CELL DEATH TRIGGERED BY CYTOTOXIC T-LYMPHOCYTES - A TARGET-CELL MUTANT DISTINGUISHES PASSIVE PORE FORMATION AND ACTIVE CELL SUICIDE MECHANISMS

The role of the target cell in its own death mediated by cytotoxic T l ymphocytes (CTL) has been controversial. The ability of the pore-formi ng granule components of CTL to induce target cell death directly has been taken to suggest an essentially passive role for the target. This view of CTL-mediated killing ascribes to the target the single role o f providing an antigenic stimulus to the CTL; this signal results in t he vectoral degranulation and secretion of pore-forming elements onto the target. On the other hand, by a number of criteria, target cell de ath triggered by CTL appears fundamentally different from death result ing from membrane damage and osmotic lysis. CTL-triggered target cell death involves primary internal lesions of the target cell that reflec t a physiological cell death process. Orderly nuclear disintegration, including lamin phosphorylation and solubilization, chromatin condensa tion, and genome digestion, are among the earliest events, preceding t he loss of plasma membrane integrity. We have tested directly the invo lvement of the target cell in its own death by examining whether we co uld isolate mutants of target cells that have retained the ability to be recognized by and provide an antigenic stimulus to CTL while having lost the capacity to respond by dying. Here, we describe one such mut ant, BW87. We have used this CTL-resistant mutant to analyze the mecha nisms of CTL-triggered target cell death under a variety of conditions . The identification of a mutable target cell element essential for th e cell death response to CTL provides genetic evidence that target cel l death reflects an active cell suicide process similar to other physi ological cell deaths.