Lymphotoxin alpha Beta and LIGHT cytokine systems

T细胞的激活和分化依赖于TCR对抗原的参与和协同信号 由几个不同的受体-配体系统提供。疱疹病毒进入介体(HVEM)，一种肿瘤坏死因子 Hvem是超家族成员，参与光对T细胞的共刺激信号，但也参与B细胞。 T淋巴细胞衰减器(BTLA)，Ig超家族成员，为T细胞提供抑制信号。 大量研究表明，hvem在阳性和抑制性之间起着分子开关的作用。 T细胞中的共信号。此外，HVEM-BTLA系统计数器作用于密切相关的LTA(3-LT|3R 系统，共同调节树突状细胞特定亚群的动态平衡和扩张。 淋巴器官。因此，了解这个细胞因子网络的调节机制应该提供 对控制免疫反应的新见解。我们发现光要么在它的膜上，要么是可溶的 位置改变HVEM与BTLA的结合，从而控制细胞 光的区域化可能影响BTLA的抑制信号。我们建议研究如何 各种形式的光调制HVEM-BTLA相互作用。具体地说，可溶性配体和 光的多态变体改变了BTLA的激活。此外，人类光线的多态变体 将检查它们对光脱落和参与膜切割的酶的影响 光将使用表达克隆策略进行识别。我们将探索类似的路径是否 对于含有保守的BTLA结合域的其他TNFR，也存在HVEM-BTLA。HVEM-BTLA在一个 有丝分裂后限制树突状细胞扩张的步骤。将检查死亡受体信号的衰减。 HVEM-BTLA抑制小鼠树突状细胞动态平衡的机制之一 和人体模型。这些计划将提供对LTAP和光信号如何的机械理解 整合在一起以协调T淋巴细胞和树突状细胞之间的细胞间通讯 免疫反应。 层面总结：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 免疫细胞之间相互通信。我们证明了改变这些分子的活性 改变细胞的反应。这一研究为进一步研究人类免疫系统的功能提供了新的契机。 自身免疫性和感染性疾病中的免疫系统

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