Role of Caspase-8 in Lymphocyte Proliferation

描述（由申请人提供）：本提案的总体目标是阐明caspase-8促进T细胞活化的机制。免疫反应的特点是淋巴细胞大量扩增以消除外来抗原，随后大量凋亡以实现体内平衡。目前尚不清楚细胞凋亡机制如何在增殖淋巴细胞中保持完整，以确保其最终死亡。caspase -8是一种对淋巴细胞凋亡至关重要的启动caspase。然而，最近的研究矛盾地表明，caspase-8也是淋巴细胞增殖所必需的。Caspase-8以潜伏形式（procaspase-8）产生，在细胞凋亡过程中，它经历两个加工事件以产生成熟的Caspase-8。我们发现这种激活是由procaspase-8寡聚化引发的，涉及到加工中间体的产生，这些中间体具有蛋白水解能力，但在酶学上不同于完全加工的成熟caspase-8。在淋巴细胞活化过程中，procaspase-8与Bcl10和MALT1形成的复合物相关，两者都是抗原信号传导的关键介质。我们将1)建立控制淋巴细胞增殖过程中procaspase-8激活的机制，2)确定促进淋巴细胞增殖的procaspase-8的形式，以及3)鉴定和表征增殖形式caspase-8的底物。凋亡蛋白嵌入细胞增殖通路有效地将淋巴细胞的生与死的控制联系起来。因此，该研究将揭示这两个基本免疫细胞过程之间的相互作用，并将对基于caspase的治疗过度增殖和免疫系统缺陷具有实际意义。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to elucidate the mechanism by which caspase-8 promotes T cell activation. Immune responses are characterized by massive expansion of lymphocytes to eliminate foreign antigens, followed by massive apoptosis to achieve homeostasis. It remains unclear how the apoptotic machinery is kept intact in proliferating lymphocytes to ensure their ultimate demise. Caspase-8 is an initiator caspase critical for lymphocyte apoptosis. However, recent studies indicate that paradoxically, caspase-8 is also required for lymphocyte proliferation. Caspase-8 is made in latent form (procaspase-8), and during apoptosis it undergoes two processing events to generate mature caspase-8. We have found that this activation is triggered by procaspase-8 oligomerization and involves the generation of processing intermediates that are proteolytically competent but enzymatically different from the fully processed mature caspase-8. During lymphocyte activation, procaspase-8 becomes associated with a complex formed by Bcl10 and MALT1, both being critical mediators of antigenic signaling. We will 1) establish the mechanism that controls procaspase-8 activation during lymphocyte proliferation, 2) determine the form of procaspase-8 that promotes lymphocyte proliferation, and 3) identify and characterize the substrates of the proliferative form of caspase-8. The embedment of an apoptotic protein into the cell proliferative pathway effectively links the control of lymphocyte life and death. The proposed study will thus shed important light on the interplay between these two fundamental cellular processes in immunity, and will have practical implications for caspase-based therapy for hyperproliferation and deficiency of the immune system.