Lymphotoxin alpha Beta and LIGHT cytokine systems

T细胞的活化和分化依赖于抗原的TCR接合和协同信号 由几种不同的受体-配体系统提供。疱疹病毒进入介质（HVEM），一种TNF HVEM是超家族成员，与LIGHT结合，启动对T细胞的共刺激信号，而HVEM也与B结合 和T淋巴细胞衰减因子（BTLA），一种向T细胞提供抑制信号的IG超家族成员。 实质性的进展表明HVEM作为一个分子开关之间的积极和抑制 T细胞中的共同信号。此外，HVEM-BTLA系统对抗密切相关的LTa（3-LT| 3R 系统，共同调节体内特定树突细胞亚群的稳态和扩增， 淋巴器官因此，了解这种细胞因子网络的调节机制， 控制免疫反应的新见解我们发现，无论是在其膜或可溶性光 位置改变HVEM与BTLA的结合，因此控制细胞凋亡的机制是通过改变HVEM与BTLA的结合来实现的。 LIGHT的区室化可影响BTLA的抑制性信号传导。我们建议研究如何 各种形式的LIGHT调节HVEM-BTLA相互作用。特别是可溶性配体和 LIGHT的多态性变体修饰BTLA的活化。此外，人类LIGHT的多态性变体 将检查它们对光脱落和参与膜裂解的酶的影响 将使用表达克隆策略鉴定LIGHT。我们将探索类似的途径 与HVEM-BTLA相比，其他含有保守BTLA结合结构域的TNFR存在差异。HVEM-BTLA作用于 有丝分裂后步骤，以限制树突状细胞扩增。将检查死亡受体信号传导的衰减 作为介导HVEM-BTLA对树突状细胞稳态的抑制作用的一种机制，使用小鼠 和人体模型。这些计划将提供一个机械的理解如何LTap和光信号 整合以协调T淋巴细胞和树突细胞之间的细胞间通讯， 免疫反应。 我们的研究确定了一组重要的分子，称为细胞因子，它们控制着 免疫细胞之间相互交流。我们证明了改变这些分子的活性 改变细胞的反应。这项研究为改变细胞的功能提供了一个新的机会。 自身免疫性疾病和感染性疾病中免疫系统

T cell activation and differentiation is dependent on TCR engagement of antigen and cooperating signals provided by several distinct receptor-ligand systems. The herpesvirus entry mediator (HVEM), a TNF superfamily member, engages LIGHT initiating costimulatory signals to T cells, yet HVEM also engages B and T lymphocyte attenuator (BTLA), an Ig superfamily member that provides an inhibitory signal to T cells. Substantial progress indicates that HVEM acts as a molecular switch between positive and inhibitory cosignaling in T cells. Moreover, the HVEM-BTLA system counter acts the closely related LTa(3-LT|3R system, which together regulates the homeostasis and expansion of specific subsets of dendritic cells in lymphoid organs. Thus understanding the regulatory mechanisms of this cytokine network should provide new insight into controlling immune responses. We found that LIGHT in either its membrane or soluble position modifies the binding of HVEM to BTLA, thus the mechanisms controlling the cellular compartmentalization of LIGHT may influence inhibitory signaling by BTLA. We propose to examine how various forms of LIGHT modulate the HVEM-BTLA interaction. Specifically how soluble ligands and polymorphic variants of LIGHT modify activation of BTLA. In addition, polymorphic variants of human LIGHT will be examined for their influence on LIGHT shedding and the enzyme involved in cleavage of membrane LIGHT will be identified using an expression cloning strategy. We will explore whether analogous pathways to HVEM-BTLA exist for other TNFR containing the conserved BTLA binding domain. HVEM-BTLA acts at a postmitotic step to limit dendritic cell expansion. The attenuation of death receptor signaling will be examined as one mechanism mediating the inhibitory affect of HVEM-BTLA on dendritic cell homeostasis using mouse and human models. These plans will provide a mechanistic understanding of how LTap and LIGHT signals are integrated to orchestrate intercellular communication between T lymphocytes and dendritic cells during immune responses. Lay summary: Our research identified an important set of molecules, termed cytokines, that control how immune cells communicate with each other. We demonstrated that altering the activity of these molecules changes the responses of cells. This research provides a new opportunity to modify the function of the immune system in autoimmune and infectious diseases