ACTIVATION OF TARGET CELL SUICIDE IN THE IMMUNE SYSTEM

正常情况下使用的基本调节机制之一 健康生物体的发育和体内平衡涉及 消除某些细胞和组织。 过程中 免疫反应，病毒感染，转化，以及其他 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操纵，免疫系统 提供了一个很好的模型，为研究的过程， 哪些细胞被触发死亡。 我们的遗传学研究表明，靶细胞具有可变的 对细胞毒性T细胞的细胞溶解反应所必需的元素 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 被认为是合适的目标。 相同的自杀途径 在未成熟的胸腺细胞中， 皮质类固醇激素，并可能参与自然 胸腺细胞亚群的死亡 个体发育 值得注意的是，该途径似乎并不 参与补体依赖性细胞死亡 抗体介导的裂解。 在这个提议中，概述了将探索 自杀途径在免疫中的激活过程。 该途径 假设由若干步骤组成;这些要素 将通过遗传和生化分析来确定其特征。 这种自杀过程在其他免疫反应中的相关性 将探索，通过测试CTL抗性的敏感性， “不死”突变体对其他免疫效应物的裂解，例如 自然杀伤细胞和细胞溶解因子。 这项研究也可能 提供对免疫淋巴细胞个体发育、体内肿瘤 和病毒控制，以及其他细胞死亡的例子 哺乳动物的发育。

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.