ACTIVATION OF TARGET CELL SUICIDE IN THE IMMUNE SYSTEM

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One of the basic regulatory mechanisms employed in the normal development and homeostasis of healthy organisms involves the elimination of certain cells and tissues. During the course of immune responses, virally infected, transformed, and otherwise inappropriate cells are also targets of cytolytic events. Because these cytolytic events are easily manipulated, the immune system provides an excellent model for the study of the processes by which cells are triggered to die. Our genetic studies suggest that target cells possess mutable elements necessary for the cytolytic response to cytotoxic T lymphocytes (CTL). These "response" elements may identify a cellular suicide process that can be triggered by CTL in cells recognized as appropriate targets. The same suicide pathway seems also to be activated in immature thymocytes by corticosteroid hormones and may be involved in the naturally occurring death of thymocyte subpopulations during thymic ontogeny. Significantly, the pathway does not appear to be involved in the death of cells caused by complement-dependent antibody-mediated lysis. In this proposal, experiments are outlined which will explore the process of suicide pathway activation in immunity. The pathway is hypothesized to consist of a number of steps; these elements will be characterized through genetic and biochemical analyses. The relevance of this suicide process in other immune responses will be explored, by testing the sensitivity of the CTL resistant "deathless" mutants to lysis by other immune effectors, such as natural killer cells and cytolytic factors. This study may also provide insight into immune lymphocyte ontogeny, in vivo tumor and virus control, as well as other instances of cell death programming in mammalian development.