Regulation of NF-kB by TCR and costimulatory signaling

该项目将通过研究TCR信号传导的手臂， 活化NF-κ B，一种抗原诱导的T细胞增殖和活化所需的转录因子。 TCR信号传导至NF-κ B的研究提供了几个机会来扩展我们对T细胞如何通过免疫调节作用的理解。 细胞解释抗原输入。首先，对TCR如何激活NF-κ B的机制的理解还远未完全清楚。 从完成。这一途径的关键组成部分仍未被发现， 该途径也将在该计划研究的TCR信号传导的其他分支中发挥重要作用。在AIM 1中， 我们将使用一种新的表达克隆策略来鉴定TCR信号的增强子和抑制子， NF-κ B。第二，最大的TCR介导的NF-κ B活化需要TCR与MHC结合， 抗原（信号1）和共刺激信号（信号2）。在AIM 2中，我们将测试CARD 11- GADS相互作用是CD 28介导的NF-κ B共刺激信号传导所必需的。第三，虽然很明显， 从TCR向NF-κ B发信号的分子以动态， 虽然这是一种受监管的方式，但不清楚如何以及为什么要做到这一点。在AIM 3中，我们将研究如何 NF-κ B信号传导中间体被募集到免疫突触。该项目将受益于 与项目中其他项目的协同作用。AIM 1将使用核心C，并应产生新的组件， 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）的形成和调节，Sprouty！介导的调节和钙 信号，分别。AIM 2可以提供分子洞察T细胞如何进行细胞选择， 激活或无反应性，并将应用小鼠模型和J.鲍威尔的专业知识（项目3）。AIM 3将使用 核心B和A开发的技术。Kupfer（项目2），并将有助于理解IS T细胞激活期间的形成和结构。我们的研究结果应该有助于理解 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，并作出适当的反应。由于对刺激的不当反应会导致 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， 设计用于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.