We found that the cytotoxic T lymphocyte (CTL) initiates a lesion in its target cell that causes the destruction not only of the target cell membrane but also the target cell nucleus. This unique lesion is not a general phenomenon in most other forms of target cell death including Ab+C mediated lysis and lysis mediated by hypotonic shock. Since the major role of the CTL in vivo is the destruction of virally altered (either infectious or oncogenic) cells, we have suggested that this lesion may have significance in increasing the CTL's overall efficiency. The proposed studies will focus on the primary events within the target that lead to the expression of the nuclear lesion. The earliest, quantifiable nuclear change is the sensitivity of the target cell nucleus to nonionic detergents. Therefore early studies will be directed at physical changes in the structural proteins of the nuclear membrane that impart resistance to nonionic detergent. Changes in the phosphorylated state of these proteins are associated with the structural reorganization of the nucleus during cell division. By the use of antisera and labeling studies we will compare the changes in nuclear and other cytoskeletal structural proteins with those observed during mitosis. Thus, we will test the hypothesis that the nuclear lesion is the result of the delivery of an inappropriate signal for cell division from the CTL to the target. Additional experiments will test the hypothesis that the CTL-target interaction can be defined within the CTL, in biochemical and physiological terms, as the receptor-stimulated local accumulation of inositol phosphates which are cleaved leaving a membrane bound diacyl glycerol as initiation site for the local secretion of lytic effector molecules. Preliminary evidence suggests that phorbol diesters may mimic the physiological situation and allow the identification of lytic effector molecules. (LB)
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