ACTIVATION OF CELL SUICIDE IN THE IMMUNE SYSTEM

活化驱动的T细胞死亡似乎代表了 体内克隆删除，T细胞的主要机制 宽容是实现的。对过程的刻画 未转化成熟T细胞体外激活诱导的细胞死亡 在转化的T细胞杂交瘤中已经证明了死亡的细胞 在自身的死亡中扮演着积极的角色。激活驱动的细胞死亡 以细胞自主的方式发生，对未受刺激的 旁观者细胞。这个过程依赖于大分子的合成， 推测反映了参与基因的特定表达 细胞自杀过程。对激活驱动的细胞死亡的易感性是 发育调节的。我们对关键事件的分析在这个和 其他生理性细胞死亡的案例使我们认为细胞 自杀代表着一个类似有丝分裂的流产过程的诱导。 本文提出的研究将探索激活驱动的T的过程 分子水平上的细胞死亡。我们将定义以下方面的要求 未成熟T细胞和WE诱导活化诱导细胞死亡 将表征对T细胞施加的发育控制 影响阳性克隆和阴性克隆的细胞死亡易感性 选择。我们将研究激活驱动的细胞死亡过程 从机制上探讨有丝分裂样激酶的参与 对细胞至关重要的磷酸化依赖事件的活性 死亡，特别是核膜溶解和细胞骨架 重组。我们将测试这些活动是否代表 正宗的细胞分裂控制基因产品上的生化和 遗传水平。 对心力衰竭的发病机制和生理调节的认识 免疫中激活驱动的细胞死亡过程将提供洞察力 淋巴细胞个体发生的调控与自身免疫的选择 反应性，以及体内肿瘤控制的潜在机制。

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.