Regulation of NF-kB by TCR and costimulatory signaling

该项目将通过调查TCR的ARM信号来为该计划的总体目标做出贡献 激活核因子-KB，这是一种转录因子，是抗原诱导的T细胞增殖和激活所必需的。 TCR信号转导核因子-KB的研究为我们提供了几个机会来扩大我们对T是如何 细胞解释抗原输入。首先，对TCR如何激活核因子-KB的机械性理解还很遥远 从完整开始。这条途径的关键组成部分仍未被发现，很可能是新的参与者 这一途径也将在本计划研究的TCR信号的其他分支中发挥重要作用。在目标1中， 我们将使用一种新的表达克隆策略来识别TCR信号的增强子和抑制子，以 核因子-KB。其次，最大限度的TCR介导的NF-KB激活需要MHC和MHC两种TCR参与 抗原(信号1)和共刺激信号(信号2)。在目标2中，我们将检验CARD11- CD28介导的共刺激信号转导核因子-KB需要GADS相互作用。第三，虽然很明显 从TCR到核因子-KB的信号分子以动态的方式被招募到免疫突触(IS)， 尽管这是一种受监管的方式，但尚不清楚这究竟是如何实现的，以及实现的原因。在AIM 3中，我们将研究如何 核因子-KB信号中间产物被招募到免疫突触中。这个项目将受益于 与计划中其他项目的协同效应。AIM 1将使用核心C，并应产生新的组件或 TCR信号通路的调节器，可在项目1、2、3和4中研究其在TCR中的作用 聚集、免疫突触(IS)的形成和调节、Sprouty！介导的调节和钙 分别发信号。AIM 2可能为T细胞如何进行细胞选择提供分子洞察力 激活或无能，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(项目2)开发的技术，将有助于理解IS T细胞活化过程中的形成和结构。我们的结果应该会加深人们对 免疫细胞的分子机制可以识别和解释环境信号，包括致病因素 和非致病刺激，并做出适当的反应。因为对刺激的不适当反应可能会导致 在无效的免疫监测、自身免疫或癌症中，我们的结果可能为新的 用来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.