Activation-driven T cell death appears to represent the mechanism of clonal deletion in vivo, the principle mechanism by which T cell tolerance is achieved. Characterization of the process of activation-driven cell death in vitro in non-transformed, mature T cells and in transformed T cell hybridomas has demonstrated that the dying cell plays an active role in its own death. Activation-driven cell death occurs in a cell-autonomous manner, without effect on unstimulated bystander cells. This process is dependent on macromolecular synthesis, presumably reflecting the specific expression of genes involved in the cell suicide process. Susceptibility to activation-driven cell death is developmentally regulated. Our analyses of critical events in this and other cases of physiological cell death have led us to suggest that cell suicide represents the induction of an abortive mitosis - like process. The studies proposed here will explore the process of activation-driven T cell death on the molecular level. We will define the requirements for the induction of activation-driven cell death in immature T cells and we will characterize the developmental controls exerted on T cell susceptibility to cell death which influence positive and negative clonal selection. We will examine the activation-driven cell death process mechanistically by exploring the involvement of mitosis-like kinase activities in the phosphorylation-dependent events critical to cell death, especially nuclear envelope dissolution and cytoskeletal reorganization. We will test whether these activities represent authentic cell division control gene products on both the biochemical and genetic levels. An understanding of the mechanism and the physiological regulation of the process of activation-driven cell death in immunity will provide insight into the control of lymphocyte ontogeny and selection against autoimmune reactivity, as well as potential mechanisms of in vivo tumor control.
