In Vivo Function of the B7 Family of Costimulators

本应用程序的总体目标是剖析最近确定的B7/CD28家族的功能角色 ICOS和PD-L1在调节粘膜耐受中的作用。这一焦点是由我们最近的研究推动的， 已经确定了ICOS和PD-L1在粘膜耐受中的基本、非多余的作用。我们发现， ICOS和PD-L1在控制口服诱导的调节性T细胞发挥其功能方面具有相似的作用 起到保护作用。这些角色中的每一个都必须是唯一的，因为口服诱导的WT CD4+Treg不能发挥作用 转移到ICOS-/-或PD-L1-/-小鼠后。相比之下，需要PD-L1，但不需要ICOS 产生功能性口服诱导的CD4+Treg。探讨ICOS与帕金森病的关系 在调节粘膜耐受性方面，我们将分析1)ICOS在粘膜耐受的产生和/或功能中的作用 致病效应T细胞(IL-12驱动的产生干扰素-γ的Th1细胞和IL-23驱动的ThlL-17细胞)，因为 口服诱导的WT CD4+T reg功能受损可能是原发缺陷或继发于增强 ICOS-/-效应细胞的致病性2)ICOS在调节口服诱导的CD4+Treg功能中的作用； 3)ICOS和PD-L1在控制自身反应效应器和口腔功能中的关系 诱导的CD4+T细胞亚群。这些研究应该揭示ICOS和PD-L1在控制血管生成中的相对作用。 体内调节性和生脑Th1细胞之间的平衡。我们已经收集了一些小说 将使我们能够解决这些问题的工具。为了剖析ICOS在粘膜耐受中的作用，我们有 培育出ICOS-/-小鼠。我们的PD-L1-/-小鼠将成为研究PD-L1如何调节的权威工具 口服诱导的CD4+Treg细胞的产生和功能。我们将使用MOG35-55特异性TCR转基因 ICOS和PD-L1基因异常对血管内皮细胞活化、迁移和扩张的影响 体内幼稚和效应性T细胞，以及口服诱导的Treg的发展和行为。这些研究 应该有助于深入了解ICOS和PD-L1是如何调节自身反应性T细胞的反应的。

The overall goal of this application is to dissect the functional roles of the recently identified B7/CD28 family members ICOS and PD-L1 in regulating mucosal tolerance. This focus is driven by our recent studies that have identified essential, non-redundant roles for ICOS and PD-L1 in mucosal tolerance. We have found that ICOS and PD-L1 have similar roles in controlling the ability of orally-induced regulatory T cells to exert their protective effects. Each of these roles must be unique, since orally induced WT CD4+ Treg cannot function following transfer into ICOS-/- or PD-L1-/- mice. In contrast, PD-L1, but not ICOS, is required for the generation of functional orally induced CD4+ Treg. To investigate the relationships between ICOS and PD- L1 in regulating mucosal tolerance, we will analyze the 1) role of ICOS in the generation and/or function of pathogenic effector T cells (IL-12 driven IFN-g producing Th1 cells and IL-23 driven ThlL-17 cells), since the impaired function of orally induced WT CD4+ T reg could be a primary defect or secondary to enhanced pathogenicity of ICOS-/- effector cells 2) role of ICOS in controlling function of orally induced CD4+ Treg; and 3) relationships between ICOS and PD-L1 in controlling functions of self reactive effector and orally induced CD4+ T reg. These studies should reveal the relative roles of ICOS and PD-L1 in controlling the balance between regulatory and encephalitogenic Th1 cells in vivo. We have assembled a number of novel tools that will enable us to address these issues. To dissect the role of ICOS in mucosal tolerance, we have developed ICOS-/- mice. Our PD-L1-/- mice will serve as a definitive tool to examine how PD-L1 regulates the generation and function of orally-induced CD4+ Treg. We will use MOG35-55 specific TCR transgenic mice to visualize the effects of ICOS and PD-L1 dysregulation on activation, migration and expansion of naive and effector T cells in vivo, and development and behavior of orally induced Treg. These studies should lead to insights into how ICOS and PD-L1 regulate the responses of self-reactive T cells.