ANALYSIS OF BIDIRECTIONAL SIGNALING MECHANISMS FOR BTLA AND HVEM IN AUTOIMMUNITY

描述（由申请人提供）：我们在本计划项目资助的前一个周期中克隆了新型抑制性受体B和T淋巴细胞衰减剂（BTLA），并确定其是免疫应答的重要一般调节剂。通过产生和检查BTLA敲除小鼠，我们发现BTLA在几种模型系统中调节免疫应答，包括几种自身免疫模型。我们还认识到并描述了多态性BTLA在小鼠中的影响其表达和分布。重要的是，人类BTLA的多态性最近与风湿性关节炎的易感性有关，突出了充分理解BTLA作用机制的重要性。 免疫应答的强度和持续时间的调节对于平衡针对病原体的保护性应答与作为其结果的组织损伤至关重要。抑制性受体如CTLA- 4、PD-1和BTLA可以通过确保存在用于激活免疫应答的适当阈值以及通过限制所引发的应答的强度和持续时间来促进这种平衡。 然而，关于BTLA仍然有许多基本问题没有得到解决。我们实验室最近的发现已经确定了BTLA（CD 28/B7 IG受体超家族的成员）与疱疹病毒进入介体（HVEM）（TNF受体家族成员）之间完全出乎意料和前所未有的相互作用。我们将HVEM鉴定为BTLA配体是我们先前克隆BTLA配体的目的的一部分，这一发现现在已被其他人证实。值得注意的是，BTLA和HVEM之间的结合发生在小鼠和人类系统中。虽然BTLA可能是抑制性的，但HVEM可以提供激活的促存活信号。事实上，我们最近的发现和初步数据表明了双向信号传导的证据，其具有传递抑制和促存活信号的潜力。因此，本申请旨在剖析BTLA-HVEM相互作用的两个方向，以便可以在基本水平上理解其对人类自身免疫如风湿性关节炎的贡献。我们的目标是：目标1。在不同的免疫应答和自身免疫模型中区分BTLA的细胞内在和细胞外在作用。目标二。分析BTLA中的胞质信号基序。目标3.确定BTLA、LIGHT和HVEM之间的双向相互作用以用于信号传导。 项目叙述：自身免疫是健康和人类疾病的主要问题，其起因于免疫系统耐受机制的各种模式的失败。自身免疫性疾病有多种表现，例如针对关节（关节炎）、胰腺内分泌细胞（糖尿病）或肾脏过滤机制（狼疮）的免疫反应。我们的研究旨在分析控制免疫反应的正常激活和抑制的基本机制，并专注于一个新的基因，B和T淋巴细胞衰减剂（BTLA），我们发现和克隆作为同一批以前周期的一部分。重要的是，BTLA最近被报道参与人类对类风湿性关节炎的易感性。因此，我们提出的对这种新发现但知之甚少的分子的研究特别及时。

DESCRIPTION (provided by applicant): We cloned the novel inhibitory receptor B and T Lymphocyte Attenuator (BTLA) in a previous cycle of this Program Project grant, and established that it is an important general regulator of immune responses. By generating and examining BTLA knockout mice, we found that BTLA regulates immune responses in several model systems, including several models of autoimmunity. We also recognized and described polymorphisms in BTLA in the mouse that influence its expression and distribution. Importantly, polymorphisms of BTLA in humans were recently linked to susceptibility to Rheumatoid arthritis, highlighting the importance of fully understanding the mechanism of BTLA action. Regulation of the intensity and the duration of immune responses is a critical for balancing the protective responses against pathogens with damage to tissues that are their result. Inhibitory receptors such as CTLA- 4, PD-1 and BTLA can contribute to this balance by ensuring that appropriate thresholds exist for activating the immune response, and by limiting the intensity and duration of responses that are initiated. However, there are still many basic issues about BTLA that are unresolved. Recent findings by our lab have identified a wholly unexpected and unprecedented interaction between BTLA, a member of the CD28/B7 Ig super family of receptors, with Herpesvirus entry mediator (HVEM), a TNF receptor family member. Our identification of HVEM as the BTLA ligand arose as part of our previous Aims to clone the ligand for BTLA, and this finding has now been confirmed by others. It is important to note that the binding between BTLA and HVEM occurs in the mouse and the human systems. While BTLA may be inhibitory, HVEM can provide activating, pro-survival signals. In fact, our recent findings and preliminary data indicate evidence for a bi- directional signaling, which has potential for delivering both inhibitory and pro-survival signals. Thus, the current application is aimed at dissecting both directions of the BTLA-HVEM interaction so that its contribution to human autoimmunity such as Rheumatoid arthritis can be understood at the basic level. Our aims are: Aim 1. Discriminate cell-intrinsic from cell-extrinsic actions of BTLA in distinct models of immune response and autoimmunity. Aim 2. Analyze the cytoplasmic signaling motifs in BTLA. Aim 3. Determine the bidirectional interactions between BTLA, LIGHT, and HVEM for signaling. Project Narrative: Autoimmunity is a major problem of health and human disease, which result from various modes of failure of the tolerance mechanisms of the immune system. Autoimmune diseases have many kinds of manifestations, such as immune responses that target the joints (arthritis), the endocrine cells of the pancreas (diabetes) or the filtering mechanism of the kidney (Lupus). Our study is directed at analyzing the basic mechanisms that control the normal activation and inhibition of the immune response, and are focused on a new gene, B and T Lymphocyte Attenuator (BTLA), that we discovered and cloned as a part of previous cycles of this same grant. Importantly, BTLA has recently been reported to be involved in the susceptibility in humans to rheumatoid arthritis. Thus, our proposed studies into this newly identified but poorly understood molecule are particularly timely.