Environmental control of the immunological synapse

描述(申请人提供)：淋巴结内的淋巴细胞动力学由环境信号和停止信号控制，这些信号与细胞内固有的极性网络相互作用。趋化因子受体是一类主要的G蛋白偶联受体，而CCR7是这类受体中最重要的成员，负责将GO信号传递给次级淋巴组织中的初始效应T细胞(TEF)。每个抗原受体可以与一系列效力不同的MHC-多肽复合体配体相互作用，并可以在不同浓度的不同数量的树突状细胞上呈现，以传递停止信号。到极性网络的信号部分是由蛋白激酶C-8(PKC-8)介导的，PKC-8诱导对称性破坏和稳定突触向移动突触的转换。调节性T细胞(Treg)在抗原应答时激活PKC-8，而调节性T细胞(Treg)在抗原应答时失活PKC-8，提示TCR信号对极性有明显的控制作用。我们的假设是，GO、STOP和Treg PKC-8信号的特殊配置导致外周对低效配体的耐受性失败，低效配体可以在组织损伤或炎症刺激的背景下成为自身抗原。首先，我们将确定消除GO信号对T细胞受体系统中一系列配体的TJeff反应的影响。其次，我们将研究T细胞对高效性和低效性配体反应的结构方面，并量化抗原呈递树突状细胞频率对耐受诱导的影响。第三，我们将在体内和体外研究PKC-8在控制Treg与DC和TJeff相互作用中的作用。这些研究的结果将填补我们对TJeff和Treg相互作用如何在淋巴结和效应部位调节的主要空白，这是维持外周耐受和防止自身免疫的关键。 公共卫生相关性：疫苗接种策略依赖于抗原特异性T淋巴细胞和抗原提呈树突状细胞之间的物理拥抱。我们假设，这种拥抱的稳定性将取决于抗原的质量，该抗原为迁移的T细胞定义了一个停止信号，环境中的信号为淋巴细胞提供了竞争的GO信号，以及由激酶控制的极性网络。我们建议通过实验来确定趋化因子、树突状细胞频率和调节性T细胞蛋白激酶C-8在耐受诱导中的作用。

DESCRIPTION (provided by applicant): Lymphocyte dynamics in lymph nodes are governed by environmental GO signals and STOP signals that interact with intrinsic polarity networks in the cell. Chemokine receptors are a major class of G-protein coupled receptors and CCR7 is the most important member of this class of receptors for delivering GO signals to naive effector T cells (Teff) in secondary lymphoid tissues. Each antigen receptor can interact with a spectrum of MHC-peptide complex ligands that vary in potency and can be presented over a wide range of concentrations on varying numbers of dendritic cells to deliver STOP signals. Signaling to polarity networks is mediated in part by protein kinase C- 8 (PKC-8), which induces symmetry breaking and conversion of stable synapses to mobile kinapses. While Teff cells activate PKC-8 in response to antigen, regulatory T cells (Treg) inactivate PKC-8 in response to antigen, suggesting distinct control of polarity by TCR signals. Our hypothesis is that particular configuration of GO and STOP and Treg PKC-8 signals lead to failure of peripheral tolerance to low potency ligands that can become autoantigens in the context of tissue injury or inflammatory stimuli. First, we will determine the effect of eliminating GO signals on Teff responses to a spectrum of ligands for a well-studied T cell receptor system. Second, we will examine the structural aspects of T cell responses to high and low potency ligands and quantify the impact of antigen presenting dendritic cell frequency on tolerance induction. Third, we will investigate the role of PKC-8 in control of Treg interactions with DC and Teff in vivo and in vitro. The results of these studies will fill major gaps in our understanding of how Teff and Treg interactions are regulated in lymph nodes and at effector sites, which is key maintaining peripheral tolerance and preventing autoimmunity. PUBLIC HEALTH RELEVANCE: Vaccination strategies depend upon a physical embrace between antigen specific T lymphocytes and antigen presenting dendritic cells. We hypothesize that the stability of this embrace will depend upon the quality of antigen that defines a stop signal for the migrating T cell, signals in the environment that provide a competing go signal to the lymphocyte and polarity networks controlled by kinases. We propose experiments to determine the roles of chemokines, dendritic cell frequency and regulatory T cell protein kinase C-8 in tolerance induction.