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细胞面临着许多阶段，在这些阶段中，生存、增殖和死亡之间的适当决定是至关重要的。尽管这些选择中的许多是由不同的信号转导途径调节的，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。我们发现了一个涉及FADD/Mortl的新途径，它将T细胞的凋亡控制与细胞生长控制联系起来。FADD是一种细胞质适配器分子，与死亡受体和caspase-8和-10物理相关；这种关联导致半胱天冬酶激活。通过在T细胞中表达FADD突变形式的小鼠，我们证明了这种诱导凋亡的分子对于正常T细胞对许多有丝分裂刺激的反应至关重要。我们在本提案中概述了几种方法，以更充分地了解FADD协调T细胞增殖和凋亡选择的手段。在本提案中，我们将首先确定在正常背景下分化的T细胞增殖是否需要FADD。这将使我们能够区分FADD在T细胞发育中的作用及其在成熟的外周T细胞中作为共刺激信号成分的潜力。接下来，我们将研究在表达显性阴性FADD的T细胞背景下已知信号通路的激活，以确定FADD如何参与CD4+和CD8+ T细胞增殖的建立和维持。我们还将通过将caspase-8的显性阴性形式引入原代T细胞，探讨caspase-8可能在fadd依赖性共刺激过程中发挥作用的可能性。此外，我们将研究caspase-8的不同加工过程，以了解该分子如何在T细胞反应中诱导和维持增殖，并随后增强激活诱导的细胞死亡。FADD调节T细胞增殖和凋亡的机制是一个谜。然而，很明显，这一免疫系统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，而且还将强调对逃避人类疾病至关重要的信号范式。

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.