Environmental control of the immunological synapse

描述（由申请人提供）：淋巴结中的淋巴细胞动力学受环境GO信号和STOP信号控制，这些信号与细胞中的固有极性网络相互作用。 趋化因子受体是G蛋白偶联受体的主要类别，并且CCR 7是这类受体中用于将GO信号递送至次级淋巴组织中的幼稚效应T细胞（Teff）的最重要成员。 每种抗原受体可以与一系列MHC-肽复合物配体相互作用，这些配体的效力不同，并且可以在不同数量的树突细胞上以宽范围的浓度呈递以递送STOP信号。 极性网络的信号传导部分由蛋白激酶C- 8（PKC-8）介导，其诱导对称性破缺和稳定突触向移动的激酶的转化。 虽然Teff细胞响应于抗原激活PKC-8，但调节性T细胞（Treg）响应于抗原激活PKC-8，表明TCR信号对极性的不同控制。 我们的假设是，GO和STOP以及Treg PKC-8信号的特定配置导致外周对低效力配体的耐受性失败，所述低效力配体在组织损伤或炎症刺激的背景下可以成为自身抗原。 首先，我们将确定消除GO信号对Teff响应于一个充分研究的T细胞受体系统的配体谱的影响。 其次，我们将研究T细胞对高和低效价配体的反应的结构方面，并量化抗原呈递树突状细胞频率对耐受诱导的影响。 第三，我们将研究PKC-8在体内和体外控制Treg与DC和Teff相互作用中的作用。 这些研究的结果将填补我们理解Teff和Treg相互作用如何在淋巴结和效应位点调节的主要空白，这是维持外周耐受和预防自身免疫的关键。 公共卫生相关性：疫苗接种策略依赖于抗原特异性T淋巴细胞和抗原呈递树突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，抗原定义了迁移T细胞的停止信号，环境中的信号为淋巴细胞和由激酶控制的极性网络提供了竞争性的go信号。 我们提出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.