ACTIVATION OF CELL SUICIDE IN THE IMMUNE SYSTEM

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Cell death serves a critical physiological process in organismal development and in homeostasis. In particular, it plays a pivotal role in shaping and maintaining a non-autoreactive and self-limiting immune repertoire. We have addressed the fundamental question of whether a common cell-autonomous effector mechanism pertains in distinct cases of lymphocyte cell death. We have examined death-associated events in different cell death responses in different lymphocyte cell lines, and we have exploited death-inhibitory gene products to map the order of action of the associated activities. This work has led to the identification of a thematically conserved, ordered pathway. We have defined operationally a point of death commitment by distinguishing necessary but non-lethal [modulatory] steps from those [effector] steps which cannot be dissociated from actual death. Remarkably, the requisite activities of caspases (the family of death-associated cysteine proteases), functioning in a cascade punctuated by Bcl-2, map to the modulatory phase of the process, while cyclin dependent kinase (Cdk) activity, normally associated with cell division, plays a critical role in the effector phase of cell death. Caspases serve to activate resident Cdk components. Genetic interference with caspase- dependent Cdk complexes does not alter caspase activity or other upstream events, including mitochondrial depolarization, yet it spares cells from death. The experiments proposed seek to refine this operational characterization of Cdk function through molecular, biochemical, and cellular analyses, and to identify the critical targets of lethal Cdk action. The ability of a dying cell to trigger phagocytosis without eliciting an inflammatory response likely is the overriding biological purpose of the physiological cell death process. We will extend our characterization of the caspase- and Cdk-dependent pathway of cell death with respect to the order of events involved in inducing non-inflammatory engulfment of dying cells. Just as we employed inhibitory gene products to distinguish modulatory and effector steps of the process leading to the loss of cellular integrity, we will dissect events that lead to appropriate recognition and clearance by phagocytic cells. An understanding of the regulation, mechanism, and outcome of the physiological cell death process will offer insights to normal cell and tissue development, and may provide new views of aging and treatments for pathological conditions, including autoimmune diseases and cancers.