Growth Regulation of Activated T Cells by FADD

在免疫反应的过程中，T细胞在适当的情况下面临许多阶段 在生存、扩散和死亡之间做出决定至关重要。尽管这些选择中的许多是 通过不同的信号转导途径调节，越来越明显的是，一些调节分子 这些不同的途径是共同的。我们发现了一种新的途径，包括 FADD/Mort1，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 与死亡受体和caspase-8和-10物理关联的分子；这种关联导致 半胱氨酸酶的激活。使用在T细胞中表达突变形式的FADD的小鼠，我们已经证明 这种诱导凋亡的分子对于正常的T细胞对一些有丝分裂刺激的反应是至关重要的。 我们在这项提案中概述了几种方法，以更充分地理解FADD 协调T细胞增殖和凋亡之间的选择。在这份提案中，我们将首先确定 如果FADD是在正常背景下已经分化的T细胞增殖所必需的。这将是 使我们能够区分FADD在T细胞发育中的作用及其作为一种 成熟外周T细胞中的共刺激信号成分。接下来，我们将研究KNOWN的激活 在表达显性阴性FADD的T细胞背景下的信号通路决定FADD如何 参与建立和维持增殖的CD4+和CD8+T细胞。我们还将解决 Caspase-8在FADD依赖的共刺激过程中可能通过引入 显性-阴性形式的caspase-8进入原代T细胞。此外，我们还将研究差分处理 以了解该分子如何在T细胞反应中诱导和维持增殖 然后，加强激活诱导的细胞死亡。FADD调节两者的机制 T细胞的增殖和凋亡是一个谜。然而，很明显，增殖性和凋亡性 免疫系统的这一部分的调节对于避免癌症、自身免疫至关重要 和发病机制。因此，这些拟议研究的结果不仅将揭示一个重要的 连接这两个过程的分子，但也将突出一个信号范式，这对 逃避人类疾病。

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.