Growth Regulation of Activated T Cells by FADD

描述（由申请人提供）：在免疫应答过程中，T细胞面临许多阶段，在这些阶段中，存活、增殖和死亡之间的适当决定至关重要。虽然这些选择中的许多由不同的信号转导途径调节，但越来越清楚的是，调节这些不同途径的一些分子是共同的。我们已经发现了一种涉及FADD/Mort 1的新途径，其将T细胞中的凋亡控制与细胞生长控制联系起来。FADD是与死亡受体和半胱天冬酶-8和-10物理缔合的细胞质衔接分子;这种缔合导致半胱天冬酶活化。使用在T细胞中表达突变形式的FADD的小鼠，我们已经证明，这种凋亡诱导分子对于正常T细胞对许多促有丝分裂刺激的反应性是至关重要的。我们概述了几种方法，在这个建议，以更充分地了解FADD协调T细胞增殖和凋亡之间的选择的手段。在这个提议中，我们将首先确定FADD是否是在正常背景下分化的T细胞增殖所必需的。这将使我们能够区分FADD在T细胞发育中的作用与其在成熟外周T细胞中作为共刺激信号传导组分的潜力。接下来，我们将研究在表达显性阴性FADD的T细胞的背景下已知信号通路的激活，以确定FADD如何参与增殖的CD 4+和CD 8 + T细胞的建立和维持。我们还将通过向原代T细胞中引入显性负性形式的caspase-8来解决caspase-8可能在这种FADD依赖性共刺激过程中发挥作用的潜力。此外，我们将研究caspase-8的差异处理，以了解这种分子如何诱导和维持T细胞反应中的增殖，以及后来如何增强活化诱导的细胞死亡。FADD调节T细胞增殖和凋亡的机制是一个谜。然而，很明显，免疫系统的这一区室的增殖和凋亡调节对于避免癌症、自身免疫和发病机制至关重要。因此，这些拟议研究的结果不仅将揭示连接这两个过程的重要分子，而且还将突出对人类疾病逃避至关重要的信号传导模式。

DESCRIPTION (provided by applicant): During the course of an immune response, T cells are confronted with a number of stages where appropriate decisions between survival, proliferation and death are crucial. Although many of these choices are regulated by distinct signal transduction pathways, it is becoming clear that some of the molecules regulating these disparate pathways are shared in common. We have discovered a novel pathway involving FADD/Mortl, that links apoptotic control in T cells to cellular growth control. FADD is a cytoplasmic adapter molecule that physically associates with death receptors and caspase-8 and -10; this association results in caspase activation. Using mice expressing a mutant form of FADD in T cells, we have demonstrated that this apoptosis-inducing molecule is critical for normal T cell responsiveness to a number of mitogenic stimuli. We outline several approaches in this proposal to more fully understand the means by which FADD coordinates the choice between proliferation and apoptosis in T cells. In this proposal, we will first determine if FADD is required for the proliferation of T cells that have differentiated in a normal background. This will allow us to distinguish the role of FADD in the development of T cells from its potential to act as a costimulatory signaling component in mature peripheral T cells. Next, we will study the activation of known signaling pathways in the context of T cells expressing dominant negative FADD to determine how FADD participates in the institution and maintenance of proliferating CD4+ and CD8+ T cells. We will also address the potential that caspase-8 may play a role in this FADD-dependent costimulatory process by introducing dominant-negative forms of caspase-8 into primary T cells. Further, we will study the differential processing of caspase-8 to understand how this molecule might induce and maintain proliferation in a T cell response and later, potentiate activation-induced cell death. The mechanism by which FADD regulates both proliferation and apoptosis in T cells is an enigma. However, it is clear that both proliferative and apoptotic regulation of this compartment of the immune system is crucial for the avoidance of cancers, autoimmunity and pathogenesis. Therefore, results from these proposed studies will not only shed light on an important molecule linking these two processes, but will also highlight a signaling paradigm that is critical for the evasion of human disease.