Physiological T‐Cell Death: Susceptibility is Modulated by Activation, Aging, and Transformation, but the Mechanism is Constant

It is not surprising that the recent explosion of interest in physiological cell death has been centered particularly on lymphocytes. Physiological cell death responses are singularly important in the biology of T lymphocytes, especially in the establishment and maintenance of a diverse, non-autoreactive, and self-limiting repertoire. Cell death responses can be triggered in T cells by a variety of stimuli; sensitivity to these inducers is altered as a function of differentiation, activation, aging, and transformation. The elimination of autoreactive T cells occurs by a process that involves comitogenic stimulation at high dose with antigenic and/or mitogenic agents. The control of susceptibility to this activation-driven cell death with differentiation and with prior activation provides a mechanistic explanation for the development of central and peripheral tolerance. Enhanced lymphocyte activation with aging also leads to an augmented activation-driven cell death response. However, aging does not alter cell death responses generally, and aging-associated changes in cell death responses cannot account for aging-associated immunopathology. Oncogenic transformation also alters the activation-driven cell death response by supplanting one of the required signals for activation-driven cell death. This difference provides a rationale for selective anti-tumor therapy. A single mechanism underlies all cases of physiological cell death and involves out-of-phase mitotic activity. We now know that of the two hallmarks of cell death, genome digestion is dispensable and mitotic-like events associated with cell cycle arrest are critical. T cells triggered to undergo physiological cell death arrest in a post-mitotic compartment of the cell cycle and die when they attempt a precocious and abortive mitosis.