HVEM-BTLA system in inflammation

描述(申请人提供)：细胞激活依赖于TCR识别和提供控制T细胞反应质量的积极或消极反应的协作信号系统。共信号系统正在成为增强对肿瘤或病原体的免疫反应和减轻自身免疫性疾病的重要靶点，但这些系统仍然没有得到充分的定义。共信号调节的两个主要功能群被认为是：具有Ig样折叠的受体和肿瘤坏死因子受体超家族的成员。我们发现了疱疹病毒进入介体(hvem；TNFRSF14)和B-T淋巴细胞衰减器(BTLA)之间的一条新的抑制共信号通路，连接了TNFR和Ig共信号家族。HVEM-BTLA的相互作用是通过BTLA的ITIM基序抑制T细胞活化的途径。相比之下，LIGH-HVEM通路在T细胞激活中提供了积极的共信号系统，特别是在粘膜炎症中，但LIGH-HVEM-BTLA信号的功能后果尚不清楚。我们认为，LIGH-HVEM-BTLA相互作用为调节T细胞激活提供了一个关键的控制机制，这是本应用的总体重点。已为该项目开发了各种试剂，包括特定的激动剂和拮抗剂，例如诱饵受体、用于人类系统的特定激动剂抗体和配体，以及缺乏hvem、light和BTLA的基因缺陷的小鼠。针对LIGH-HVEM-BTLA系统在T细胞活化中的作用，提出了两个目标。第一个目的是解决允许HVEM作为积极和抑制共信号之间的分子开关的结构特征。利用人类培养系统的结构和细胞-细胞相互作用模型将用于确定HVEM-BTLA相互作用的方向性，以及光如何控制BTLA和HVEM的激活。目的2旨在通过评估hVEM、BTLA或光缺乏小鼠以及OT-II和OT-I TCR转基因hVEM缺陷小鼠的反应，使用由CD4和CDS T细胞共同控制的肺部炎症的体内模型来定义Light-HVEM-BTLA系统，涉及1型或2型细胞因子。总而言之，该项目将提供一个全面的视角，以了解LIGH-HVEM-BTLA共信号系统在肺部炎症模型中的作用，为将该系统用作治疗干预提供基础。外行观众：我们发现了几种蛋白质，它们形成了白细胞之间的通讯网络，控制着炎症。改变这种通讯系统可能有助于阻止自身免疫性疾病中发生的不必要的炎症，或者增强对病毒或癌症的免疫力。

DESCRIPTION (provided by applicant): cell activation is dependent on TCR recognition and cooperating signaling systems that provide positive or negative responses governing the quality of a T cell response. Cosignaling systems are emerging as important targets to enhance the immune response to tumor or pathogens and attenuate autoimmune diseases, yet these systems remain inadequately defined. Two major functional groups of cosignaling regulators are recognized: receptors with an Ig-like fold and members of the TNF receptor superfamily. We identified a novel inhibitory cosignaling pathway between HVEM (herpesvirus entry mediator; TNFRSF14) and BTLA (B-T lymphocyte attenuator), connecting the TNFR and Ig cosignaling families. The HVEM-BTLA interaction functions as an inhibitory pathway for T cell activation through an ITIM motif of BTLA. By contrast, the LIGHT-HVEM pathway provides positive cosignaling system in T cell activation particularly in mucosal inflammation, but the functional consequences of LIGHT-HVEM-BTLA signaling are unknown. We propose the LIGHT-HVEM-BTLA interaction provides a critical control mechanism for the regulation T cell activation, which is the overall focus of this application. A variety of reagents have been developed for this project including specific agonists and antagonists, e.g., decoy receptors, specific agonist antibodies and ligands for use with human systems, and mice genetically deficient in HVEM, LIGHT, and BTLA. Two aims are proposed to address the role of LIGHT-HVEM-BTLA system in T cell activation. The first aim addresses the structural features that allow HVEM to serve as a molecular switch between positive and inhibitory cosignaling. Structural and cell-cell interaction models utilizing a human culture system will be used to define the directionality of HVEM-BTLA interaction and how LIGHT controls the activation of BTLA and HVEM. Aim 2 is directed at defining LIGHT-HVEM-BTLA system using in vivo models of lung inflammation that are controlled by both CD4 and CDS T cells, involving Type 1 or Type 2 cytokines by assessing responses in HVEM-, BTLA-, or LIGHT-deficient mice and OT-II and OT-I TCR transgenic HVEM-deficient mice. Collectively, this project will provide a comprehensive perspective on the role of LIGHT-HVEM-BTLA cosignaling system in a lung inflammation model providing the foundation for exploiting this system as a therapeutic intervention. Lay audience: We discovered several proteins that form a communication network between white bloods cells, which control inflammation. Altering this communication system may help stop unwanted inflammation that occurs in autoimmune diseases, or to enhance immunity to viruses or cancer.