ACTIVATION OF CELL SUICIDE IN THE IMMUNE SYSTEM

描述(改编自申请人的摘要)：发展和 一种非自身反应和自我限制的免疫谱系的持续功能是 依赖于持续的能力，以严格地诱导消除 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在 对T细胞受体介导的刺激的反应。激活刺激 可以触发T细胞增殖反应的物质也可以诱导细胞死亡。 在外围，最初的激活刺激诱导细胞周期转移 和包括CD95在内的激活标记的表达；仅在 随后的刺激是死亡诱导的。因此，有义务的，暂时的 有序模式调节易感性的获得 激活导致的细胞死亡。这似乎是胸腺的情况，因为 嗯，尽管激活驱动的负选择发生在 不同的、独立于CD95的进程。事件的有序顺序也是 是生理性细胞死亡过程的中心。校长 研究人员发现了一条主题保守的、顺序的死亡路径 在不同类型的细胞中由不同的自杀刺激诱导。细胞质 CED-3型天冬氨酸特异性半胱氨酸蛋白酶活性作用于台阶上游(S) 一般可被Bcl2抑制以调节死亡反应，以及核 细胞周期蛋白依赖性激酶(CDK)的活性在下游作为一种表观的 细胞死亡的效应者。类似的事件顺序似乎是 与所有生理性死亡的情况有关，尽管特定的因素 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，诱导cdk活性是 依赖于类Ced-3蛋白水解酶的激活，但不受Bcl2的抑制。 在这一应用中的实验集中在定义分子 水平，参与激活驱动的细胞死亡的有序事件。研究 旨在鉴定分子上类似Ced-3的半胱氨酸蛋白酶， 细胞周期蛋白依赖的激酶和其他反式主导活性参与 成熟T淋巴细胞和未成熟胸腺细胞的死亡反应。研究 还将细化对调节器和效应器方面的区分 这个有序的过程。拟议中的实验还将对比 细胞死亡的激活驱动的负选择途径的元件 由于正向选择失败而导致的。除了提供 淋巴细胞个体发育调控与抗病毒选择研究进展 自身免疫反应性，详细了解其发病机制 激活驱动的戴尔之死可能揭示了 活体肿瘤控制。

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.