Execution and suicide: cytotoxic lymphocytes enforce Draconian laws through separate molecular pathways.

With the ability to analyze cytotoxicity in animals deficient in effector molecules, the debate over the biological significance of individual effector pathways is finally being settled. For CD8+ cytotoxic T lymphocytes, the two primary cytotoxic pathways are mediated by the Fas ligand and perforin. The dichotomy between the two killing pathways is mirrored in the dichotomy between their biological roles: the primary function of the Fas ligand is the control of normal cell renewal by inducing programmed cell death of actively proliferating cells via the Fas pathway. This type of cell death is part of the normal endogenous homeostatic mechanism responsible for maintaining rapidly changing cell populations such as clonally expanding and contracting T cells. In contrast, the biological function of perforin and associated granule proteins is the killing and elimination of parasitized, non-compliant cells that arise as part of pathophysiological processes and may resist lysis pathways signalled to induce apoptosis. Thus, the main function of perforin and granzymes is the maintenance of immune surveillance against both exogenous and endogenous hazards.