Role of B7H4 and CD48 in EAE

总体目标是剖析最近发现的B7家族成员B7-H4和SLAM家族成员CD48(CD2配体)在调节器官特异性方面的功能作用 自身免疫性疾病。这一焦点是由最近对多发性硬化症和小鼠1型糖尿病的遗传学研究驱动的，这些研究表明，包含这些与疾病易感性有关的共刺激分子(人或小鼠同源物)的遗传位点，以及我们最近的研究，指出B7-H4和CD48在调节T细胞激活和 宽容。为了研究B7-H4和CD48介导的信号在反应的传入臂中的作用，其中T细胞在外围被激活，以及在效应臂中，潜在的致病T细胞被驱动以介导组织破坏，我们提出了一种多方面的方法。我们将1)研究B7-H4在调节T细胞耐受和自身免疫中的作用；2)分析CD48在调节EAE的诱导期和效应期中的作用；3)研究CD48和B7-H4在调节T和B细胞耐受中的作用。我们汇集了一些新的工具，使我们能够处理这些重要问题。为了分析B7-H4在EAE中的作用，我们研制了B7-H4lg和抗B7-H4单抗。我们也 有可用的B7-H4-/-小鼠，并正在培育可诱导表达B7-H4的转基因小鼠。我们的CD48-/-小鼠和抗CD48单抗将成为研究CD48在EAE中的作用的权威工具。我们将使用MOG 35-55特异性TCR转基因小鼠来可视化 研究B7-H4和CD48在体内对幼稚和活化T细胞的激活、迁移和扩增的影响，以及MOG35-55TCR×Th双转基因小鼠，分析B7-H4和CD48在调节B细胞和T细胞对MOG耐受性中的作用。综上所述，这些研究应该有助于深入了解B7-H4和CD48共刺激如何调节自身反应性T细胞的反应。

The overall goal is to dissect the functional roles of the recently identified B7 family member, B7-H4, and the SLAM family member, CD48 (a CD2 ligand), in regulating organ-specific autoimmune diseases. This focus is driven by recent genetic studies of Multiple Sclerosis and murine type 1 diabetes that have implicated the genetic locus that contains these costimulatory molecules (human or mouse homologues) with disease susceptibility, together with our recent studies that point to important roles for B7-H4 and CD48 in regulating T cell activation and tolerance. To investigate the roles of B7-H4 and CD48-mediated signals in the afferent arm of the response where T cells become activated in the periphery, and in the effector arm, where potentially pathogenic T cells are driven to mediate tissue destruction, we are proposing a multifaceted approach. We will 1)investigate the role of the B7-H4 in regulating T cell tolerance and autoimmunity; 2)analyze the role of CD48 in regulating the induction and effector phases of EAE; and 3)examine the roles of CD48 and B7-H4 in regulating T and B cell tolerance. We have assembled a number of novel tools that will enable us to address these important issues. To dissect the role of B7-H4 in EAE, we have developed B7-H4lg and anti-B7-H4 mAb. We also have available B7-H4-/- mice and are in the process of generating transgenic mice that inducibly express B7-H4. Our CD48-/- mice, and anti-CD48 mAb will serve as definitive tools for examining the role of CD48 during EAE. We will use MOG 35-55 specific TCR transgenic mice to visualize the effects of B7-H4 and CD48 dysregulation on the activation, migration and expansion of naive and activated T cells in vivo, and MOG 35-55 TCR x Th double transgenic mice to analyze the roles of B7-H4 and CD48 in regulating B and T cell tolerance to MOG. Taken together, these studies should lead to insights into how B7-H4 and CD48 costimulatory regulate the responses of self-reactive T cells.