ACTIVATION OF TARGET CELL SUICIDE IN THE IMMUNE SYSTEM

在正常情况下使用的基本监管机制之一 健康生物体的发育和动态平衡涉及 消除某些细胞和组织。在…的过程中 免疫反应，病毒感染，转化和其他 不适当的细胞也是细胞溶解事件的目标。因为 这些细胞溶解事件很容易被操纵，免疫系统 为研究这些过程提供了一个极好的模型 哪些细胞被触发死亡。 我们的遗传学研究表明，靶细胞具有可变性 细胞毒性T细胞的溶细胞反应所必需的要素 淋巴细胞(CTL)。这些“响应”元素可以标识 细胞内CTL可触发的细胞自杀过程 被认为是适当的目标。同样的自杀途径 似乎在未成熟的胸腺细胞中也被激活 皮质类固醇激素和可能参与的自然 胸腺过程中胸腺细胞亚群的死亡 个体发育学。值得注意的是，这条路径似乎并不是 与补体依赖引起的细胞死亡有关 抗体介导的裂解。 在这项提案中，概述了将探索以下问题的实验 免疫中自杀途径的激活过程。这条路 假设由多个步骤组成；这些元素 将通过遗传和生化分析来确定其特征。 自杀过程与其他免疫反应的相关性 将通过测试CTL抗性的敏感度来探索 “不死的”突变体被其他免疫效应器裂解，例如 自然杀伤细胞和细胞溶解因子。这项研究还可能 洞察免疫淋巴细胞个体发生，体内肿瘤 和病毒控制，以及其他细胞死亡的情况 哺乳动物发育中的编程。

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.