Regulation of NF-kB by TCR and costimulatory signaling

该项目将通过研究 TCR 信号臂来促进该计划的总体目标 激活 NF-KB，这是抗原诱导 T 细胞增殖和激活所需的转录因子。 TCR 信号传导至 NF-KB 的研究提供了多种机会来扩展我们对 T 细胞如何发挥作用的理解。 细胞解释抗原输入。首先，对于TCR如何激活NF-KB的机制了解还很远。 从完成。该途径的关键组成部分仍未被发现，并且很可能有新的参与者 该通路还将在该计划研究的 TCR 信号传导的其他方面发挥重要作用。在目标 1 中， 我们将使用一种新的表达克隆策略来鉴定 TCR 信号传导的增强子和抑制子 NF-KB。其次，最大的 TCR 介导的 NF-KB 激活需要 MHC 和 TCR 的参与 抗原（信号 1）和共刺激信号（信号 2）。在 AIM 2 中，我们将测试 CARD11- CD28 介导的 NF-KB 共刺激信号传导需要 GADS 相互作用。第三，虽然很明显 从 TCR 向 NF-KB 发出信号的分子被招募到免疫突触 (IS)，以动态、 监管方式，目前尚不清楚这是如何以及为何精确实现的。在 AIM 3 中，我们将研究如何 NF-KB 信号传导中间体被招募到免疫突触。该项目将受益于 与该计划中其他项目的协同作用。 AIM 1 将使用 Core C 并且应该产生新颖的组件或 TCR 信号通路调节剂，可在项目 1、2、3 和 4 中研究其在 TCR 中的作用 聚类、免疫突触 (IS) 形成和调节、Sprouty! 介导的调节和钙 分别发出信号。 AIM 2 可以从分子角度洞察 T 细胞如何做出细胞选择 激活或无反应，并将应用小鼠模型和 J. Powell 的专业知识（项目 3）。 AIM 3将使用 核心 B 和 A. Kupfer 开发的技术（项目 2）将有助于理解 IS T 细胞激活过程中的形成和结构。我们的结果应该有助于理解如何 免疫细胞的分子机制可以识别和解释环境线索，包括致病性 和非致病性刺激，并做出适当反应。由于对刺激的不当反应可能会导致 在无效的免疫监视、自身免疫或癌症中，我们的结果可能会产生新的分子靶点 旨在治疗免疫系统疾病的疗法。

This Project will contribute to the overall goals of the Program by investigating the arm of TCR signaling that activates NF-KB, a transcription factor that is required for antigen-induced T cell proliferation and activation. The study of TCR signaling to NF-KB offers several opportunities to expand our understanding of how a T cell interprets antigenic inputs. First, the mechanistic understanding of how the TCR activates NF-KB is far from complete. Critical components of this pathway remain undiscovered and it is likely that new players in this pathway will also play important roles in other arms of TCR signaling studied in the Program. In AIM 1, we will use a novel expression cloning strategy to identify enhancers and suppressors of TCR signaling to NF-KB. Second, maximal TCR-mediated NF-KB activation requires both TCR engagement by MHC plus antigen (signal 1) and costimulatory signals (signal 2). In AIM 2, we will test the hypothesis that the CARD11- GADS interaction is required for CD28-mediated costimulatory signaling to NF-KB. Third, while it is clear that molecules that signal from the TCR to NF-KB are recruited to the immunological synapse (IS) in a dynamic, regulated manner, it is unclear how and why this is precisely accomplished. In AIM 3, we will investigate how NF-KB signaling intermediates are recruited to the immunological synapse. This project will benefit from synergy with other projects in the Program. AIM 1 will use Core C and should yield novel components or modulators of TCR signaling pathways that can be studied in Projects 1, 2, 3, and 4 for roles in TCR clustering, Immunological Synapse (IS) formation and regulation, Sprouty!-mediated regulation, and calcium signaling, respectively. AIM 2 may offer molecular insight into how a T cell makes the cellular choice of activation or anergy, and will apply a mouse model and the expertise of J. Powell (Project 3). AIM 3 will use Core B and technology developed by A. Kupfer (Project 2) and will contribute to the understanding of IS formation and structure during T cell activation. Our results should add to the understanding of how the molecular machinery of immune cells can recognize and interpret environmental cues, including pathogenic and nonpathogenic stimuli, and respond appropriately. Since the inappropriate response to stimuli can result in ineffective immune surveillance, autoimmunity, or cancer, our results may yield molecular targets for new therapies designed to treat diseases of the immune system.