ACTIVATION OF CELL SUICIDE IN THE IMMUNE SYSTEM

活化驱动的T细胞死亡似乎代表了 体内克隆缺失，T细胞 宽容是实现的。 工艺表征 体外非转化成熟T细胞中激活驱动的细胞死亡 在转化的T细胞杂交瘤中已经证明， 在自己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 该过程依赖于大分子合成， 这可能反映了参与基因表达的特异性。 细胞自杀过程 对激活驱动的细胞死亡的敏感性是 发展规律。 我们对这一时期关键事件的分析， 其他生理性细胞死亡的案例使我们认为， 自杀代表了一种类似有丝分裂的过程的诱导。 本研究将探讨激活驱动T细胞的过程， 在分子水平上的细胞死亡。 我们将定义以下要求： 在未成熟T细胞中诱导活化驱动的细胞死亡， 将描述对T细胞的发育控制， 对细胞死亡敏感性影响阳性和阴性克隆 选择. 我们将研究激活驱动的细胞死亡过程 通过探索有丝分裂样激酶的参与机制 磷酸化依赖性事件中的活性对细胞 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 真实的细胞分裂控制基因产物的生化和 基因水平。 了解其作用机制和生理调节， 免疫中激活驱动的细胞死亡过程将提供深入了解 控制淋巴细胞个体发育和选择抗自身免疫 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.