HVEM-BTLA system in inflammation

描述（由申请人提供）：细胞活化依赖于TCR识别和提供控制T细胞应答质量的阳性或阴性应答的协同信号传导系统。共信号系统正在成为增强对肿瘤或病原体的免疫应答和减轻自身免疫性疾病的重要靶点，但这些系统仍然没有充分定义。共信号调节剂的两个主要功能组是公认的：具有Ig样折叠的受体和TNF受体超家族的成员。我们发现了一个新的抑制性共信号通路之间的HVEM（疱疹病毒进入介质; TNFRSF 14）和BTLA（B-T淋巴细胞衰减剂），连接TNFR和IG共信号家族。HVEM-BTLA相互作用通过BTLA的ITIM基序作为T细胞活化的抑制途径发挥作用。相比之下，LIGHT-HVEM途径在T细胞活化中提供了阳性共信号传导系统，特别是在粘膜炎症中，但LIGHT-HVEM-BTLA信号传导的功能后果是未知的。我们提出LIGHT-HVEM-BTLA相互作用为调节T细胞活化提供了关键的控制机制，这是本申请的总体重点。已经为该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、用于人类系统的特异性激动剂抗体和配体，以及HVEM、LIGHT和BTLA遗传缺陷的小鼠。提出了两个目的来解决LIGHT-HVEM-BTLA系统在T细胞活化中的作用。第一个目标是解决的结构特征，使HVEM作为一个积极的和抑制性的共同信号之间的分子开关。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涉及使用肺部炎症的体内模型来定义LIGHT-HVEM-BTLA系统，所述肺部炎症由CD 4和CD 8 T细胞两者控制，涉及1型或2型细胞因子，通过评估HVEM-、BTLA-或LIGHT-缺陷型小鼠以及OT-II和OT-I TCR转基因HVEM-缺陷型小鼠中的应答。总的来说，该项目将提供一个全面的视角，在肺部炎症模型中的LIGHT-HVEM-BTLA共信号系统的作用，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，它们在控制炎症的白色血细胞之间形成了一个通信网络。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.