Role and mechanism of negative costimulatory pathways in EAE

EAE是由髓鞘抗原特异性致脑炎性CD 4 + Th 1细胞引发的中枢神经系统炎性疾病。在遇到抗原后，T细胞通过TCR接收信号1，并通过“阳性”共刺激分子接收信号2，导致完全激活。其他共刺激分子如CTLA 4为T细胞活化提供负信号（共抑制），并且对于终止免疫应答可能是重要的。最近，已经描述了向T细胞提供负信号的其他途径，PD 1-PDL 1/2途径以及B7-H3和B7-H4途径。本研究的主要目的是探讨PDL 1/PDL 2和B7 H3、B7 H4在EAE中的免疫调节机制。我们有独特的试剂（单克隆抗体和融合蛋白）和动物模型（基因敲除和TCR转基因动物），使我们能够剖析这一途径在临床相关疾病模型中的作用。我们将使用这些工具来研究以下内容：目的1：PDL 1和PDL 2的免疫调节机制。我们将研究的假设，PDL 1和PDL 2提供特定的信号，以各种T细胞谱系，以及效应与记忆细胞。我们将调查的假设，表达的PDL 1或PDL 2在中枢神经系统（CNS）是保护和治疗的潜力，这一途径，它是否可以配合共刺激信号阻断。目的2：探讨B7-H3和B7-H4的免疫调节机制及其在脑实质表达的意义。我们的假设是B7-H3和B7-H4途径通过在CNS实质细胞和APC上表达在调节EAE中起重要作用。我们将研究这些途径在Th 1，Th 2和Th 17细胞以及效应与记忆T细胞中的功能。我们还将研究这一途径的治疗潜力，以确定它是否可以与阻断阳性共刺激信号合作。

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.