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信号的控制，这些信号与细胞内的固有极性网络相互作用。趋化因子受体是一类主要的g蛋白偶联受体，CCR7是这类受体中最重要的成员，用于将氧化石墨烯信号传递给次要淋巴组织中的幼稚效应T细胞（Teff）。每个抗原受体都可以与一系列mhc肽复合物配体相互作用，这些配体的效力各不相同，并且可以在不同数量的树突状细胞上以大范围的浓度呈现，以传递停止信号。传递给极性网络的信号部分由蛋白激酶C-8 （PKC-8）介导，PKC-8诱导稳定突触的对称性破坏和向移动突触的转化。Teff细胞激活PKC-8以响应抗原，而调节性T细胞（Treg）灭活PKC-8以响应抗原，表明TCR信号对极性的不同控制。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，这些配体可以在组织损伤或炎症刺激的情况下成为自身抗原。首先，我们将确定消除氧化石墨烯信号对T细胞受体系统对一系列配体的Teff反应的影响。其次，我们将研究T细胞对高效和低效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性诱导的影响。第三，我们将在体内和体外研究PKC-8在控制Treg与DC和Teff相互作用中的作用。这些研究的结果将填补我们对Teff和Treg相互作用如何在淋巴结和效应位点调节的理解的主要空白，这是维持外周耐受性和预防自身免疫的关键。

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.