HVEM-BTLA system in inflammation

描述（由申请人提供）：细胞激活依赖于TCR识别和合作信号系统，这些信号系统提供控制T细胞反应质量的积极或消极反应。共同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。共信号调节因子的两个主要功能组被识别：具有ig样折叠的受体和TNF受体超家族的成员。我们在HVEM（疱疹病毒进入介质；TNFRSF14）和BTLA （B-T淋巴细胞衰减剂）之间发现了一种新的抑制性共信号通路，连接了TNFR和Ig共信号传导家族。HVEM-BTLA相互作用通过BTLA的ITIM基序作为T细胞激活的抑制途径。相比之下，LIGHT-HVEM通路在T细胞激活特别是粘膜炎症中提供了积极的共信号系统，但LIGHT-HVEM- btla信号的功能后果尚不清楚。我们提出LIGHT-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。为此项目开发了多种试剂，包括特异性激动剂和拮抗剂，例如诱饵受体、用于人体系统的特异性激动剂抗体和配体，以及HVEM、LIGHT和BTLA基因缺陷的小鼠。针对LIGHT-HVEM-BTLA系统在T细胞活化中的作用，提出了两个目标。第一个目标是解决允许HVEM作为积极和抑制性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定义HVEM-BTLA相互作用的方向性以及LIGHT如何控制BTLA和HVEM的激活。目的2旨在通过评估HVEM-、BTLA-或光照不足小鼠以及OT-II和OT-I TCR转基因HVEM-缺陷小鼠的反应，利用体内肺炎症模型定义由CD4和CDS T细胞控制的LIGHT-HVEM-BTLA系统，包括1型或2型细胞因子。总的来说，该项目将为LIGHT-HVEM-BTLA共信号系统在肺部炎症模型中的作用提供一个全面的视角，为利用该系统作为治疗干预提供基础。外行观众：我们发现了几种蛋白质，它们在白细胞之间形成一个通信网络，控制炎症。改变这种沟通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.