ACTIVATION OF CELL SUICIDE IN THE IMMUNE SYSTEM

描述（改编自申请人的摘要）： 非自身反应性和自限性免疫库的持续功能是 依赖于持续的能力，严格地诱导消除 功能不正常的淋巴细胞 删除不适当的T细胞 通过激活驱动的细胞死亡过程选择性地发生， 对T细胞受体介导的刺激的反应。 激活刺激 能引发T细胞增殖反应的基因也能诱导细胞死亡。 在外周，初始激活刺激诱导细胞周期转运 以及包括CD 95在内的活化标志物的表达;仅在 随后的刺激诱导死亡。 一个暂时的，暂时的。 有序的模式调节了易感性的获得， 激活驱动的细胞死亡。 这似乎是胸腺的情况， 好吧，尽管激活驱动的负选择是由一个 独特的、不依赖于CD 95的过程。 事件的有序序列也是 是生理细胞死亡过程的核心 校长 研究人员发现了一个主题上保守的，连续的死亡途径 在不同的自杀刺激诱导的不同细胞类型中。 细胞质 Ced-3样Asp特异性半胱氨酸蛋白酶活性在步骤上游起作用 通常可通过Bcl-2调节死亡反应， 细胞周期蛋白依赖性激酶（CDK）活性在下游起明显的 细胞死亡的效应子。 一系列类似的事件似乎 在所有的生理死亡的情况下，虽然特定的元素， 由特定自杀刺激诱导的途径可能是不同的。 在 激活驱动的细胞死亡反应，cdk活性的诱导是 依赖于Ced-3样蛋白酶激活，但不受Bcl-2抑制。 本申请中的实验集中于在分子水平上定义 水平，参与激活驱动细胞死亡的有序事件。 研究 被设计用于鉴定分子Ced-3样半胱氨酸蛋白酶， 细胞周期蛋白依赖性激酶和其他反式显性活动参与 成熟T淋巴细胞和未成熟胸腺细胞的死亡反应。 研究 还将细化的调制和效应器方面的歧视， 这个有序的过程。 拟议的实验还将对比 激活驱动的细胞死亡负选择途径的要素 这是由于积极选择的失败。 除了提供 对淋巴细胞个体发育和选择的控制的认识 自身免疫反应，详细了解的机制， 激活驱动的dell死亡可能揭示了in的潜在机制 体内肿瘤控制。

DESCRIPTION (Adapted from the Applicant's Abstract): The development and ongoing function of a non-autoreactive and self-limited immune repertoire is dependent on the persisting ability to stringently induce the elimination of functionally inappropriate lymphocytes. Deletion of inappropriate T-cells occurs selectively via the process of activation-driven cell death in response to T-cell receptor-mediated stimulation. Activating stimulation that can trigger T-cell proliferative responses also can induce cell death. In the periphery, an initial activating stimulus induces cell cycle transit and the expression of activation markers including CD95; only upon subsequent stimulation is death induced. Thus, an obligate, temporally ordered pattern regulates the acquisition of susceptibility to activation-driven cell death. This appears to be the case in the thymus as well, although activation-driven negative selection there occurs by a distinct, CD95-independent process. An ordered sequence of events also is central to the process of physiological cell death. The principal investigator has found a thematically conserved, sequential pathway of death in different cell types induced by distinct suicidal stimuli. Cytoplasmic Ced-3-like Asp-specific cysteine protease activity acts upstream of step(s) generally inhibitable by Bcl-2 to modulate the death response, and nuclear cyclin-dependent kinase (cdk) activity functions downstream as an apparent effector of cell death. A similarly ordered sequence of events appears to pertain in all cases of physiological death, although particular elements of the pathway induced by specific suicidal stimuli may be distinct. In the activation-driven cell death response, the induction of cdk activity is dependent on Ced-3-like protease activation but is not inhibited by Bcl-2. The experiments in this application focus on defining, at the molecular level, the ordered events involved in activation-driven cell death. Studies are designed to identify molecularly Ced-3-like cysteine protease, cyclin-dependent kinase, and other trans-dominant activities involved in the death response in mature T lymphocytes and in immature thymocytes. Studies will also refine the discrimination of modulatory and effector aspects of this ordered process. The proposed experiments will also contrast the elements of the activation-driven negative selection pathway to cell death resulting from a failure of positive selection. In addition to providing insight into the control of lymphocyte ontogeny and selection against autoimmune reactivity, a detailed understanding of the mechanism of activation-driven dell death may be revealing of potential mechanisms of in vivo tumor control.