Role and mechanism of negative costimulatory pathways in EAE

EAE是一种中枢神经系统炎症性疾病，由髓鞘抗原特异性的脑源性CD4+Th1细胞引发。在遇到抗原后，T细胞通过TCR接收信号1，通过“正”共刺激分子接收信号2，从而导致完全激活。其他共刺激分子，如CTLA4，为T细胞激活提供负面信号(共抑制)，并可能对终止免疫反应起重要作用。最近，已经描述了其他向T细胞提供负信号的途径，如PD1-PDL1/2途径，以及B7-H3和B7-H4途径。本研究的主要目的是探讨PDL1/PDL2和B7H3、B7H4在调节EAE中的免疫调节机制。我们拥有独特的试剂(单抗和融合蛋白)和动物模型(基因敲除和TCR转基因动物)，这将使我们能够剖析这一途径在临床相关疾病模型中的作用。我们将利用这些工具研究以下内容：目的1：PDL1和PDL2的免疫调节机制。我们将研究PDL1和PDL2向不同的T细胞系以及效应器和记忆细胞提供特定信号的假设。我们将探讨PDL1或PDL2在中枢神经系统(CNS)中的表达具有保护性的假说，以及这一通路的治疗潜力是否与共刺激信号阻断相配合。目的2：B7-H3和B7-H4的免疫调节机制及其实质表达的重要性。我们的假设是，B7-H3和B7-H4通路通过在中枢神经系统实质细胞和APC上的表达在调节EAE中发挥重要作用。我们将研究这些通路在Th1、Th2和Th17细胞中的功能，以及在效应器和记忆性T细胞中的功能。我们还将检查这一通路的治疗潜力，看看它是否可以与阻断正向协同模拟信号协同作用。

EAE is an inflammatory disease of the central nervous system initiated by myelin antigen-specific encephalitogenic CD4+ Th1 cells. After encountering antigen, T cells receive signal 1 through the TCR and signal 2 through “positive” costimulatory molecules leading to full activation. Other costimulatory molecules such as CTLA4 provide a negative signal (co-inhibitory) for T cell activation and may be important for terminating immune responses. Recently, other pathways that provides negative signaling to T cells has been described, the PD1-PDL1/2 pathway, and the B7-H3 and B7-H4 pathways. The main goal of this proposal is to explore the immune regulatory mechanisms of PDL1/PDL2 and the B7H3 and B7H4 in regulating EAE. We have unique reagents (monoclonal antibodies and fusion proteins) and animal models (gene knockout and TCR transgenic animals) that will enable us to dissect the role of this pathway in a clinically relevant disease model. We will use these tools to study the following: Aim 1: Immune regulatory mechanisms of PDL1 and PDL2. We will investigate the hypothesis that PDL1 and PDL2 provide specific signals to various T cell lineages, as well as to effector versus memory cells. We will investigate the hypothesis that expression of PDL1 or PDL2 in the central nervous system (CNS) is protective and the therapeutic potential of this pathway as to whether it could cooperate with costimulatory signal blockade. Aim 2: Immune regulatory mechanisms of B7-H3 and B7-H4 and the importance of their parenchymal expression. Our hypothesis is that B7-H3 and B7-H4 pathways play an important role in regulating EAE via expression on CNS parenchymal cells and APCs. We will examine the function of these pathways in Th1, Th2 and Th17 cells as well as in effector versus memory T cells. We will also examine the therapeutic potential of this pathway as to whether it could cooperate with blocking positive cosimulatory signals.