Role of focal CXCL10 in shaping Th1 micro-positioning and function in inflamed skin

项目摘要/摘要 感染组织内的炎症信号对于正确的效应细胞位置和功能是必要的。空间 最近有研究表明，T细胞在淋巴结内的区隔可以促进T细胞 差异化。具体地说，LNS内Th1细胞的分化依赖于CXCL10(配体 对于CXCR3，在Th1细胞上高表达)，因为它作为节点内定位的指导线索并促进 T细胞：树突状细胞在T细胞启动过程中的相互作用。然而，指示效应器T细胞空间的局部线索 一旦T细胞离开LN并进入组织感染部位，其位置和功能还知之甚少。 使用CXCL10(REX3)的报告小鼠和活体内多光子显微镜，我们可以第一次， 测定CXCL10表达细胞在原位炎症部位的分布。我们发现了一场突袭 致密的CXCL10产生细胞群与Th1细胞聚集的相关性。此外，Th1 在致密的CXCL10簇内细胞减速。我们假设空间受限的表达式 CXCL10对于Th1细胞在炎症/感染环境中的正确定位和功能至关重要。 在许多慢性感染中，由于病原体诱导对宿主的修饰，保护性免疫受到限制。 微环境。事实上，T细胞已被证明进入主要利什曼原虫密集区域的途径有限 和弓形虫感染组织中的细胞。我们的小组此前曾表示，L.大调 能主动下调感染的巨噬细胞中CXCL10的表达，巨噬细胞是真皮中的主要感染细胞。我们 假设通过限制感染细胞中CXCL10的表达，L.main干扰了正确的定位 以及有效清除病原体所需的Th1细胞的功能。 总体目标是定义影响Th1定位和/或功能的基本机制 炎症环境中富含CXCL10的显微解剖区域及CXCL10的作用 Th1细胞定位和清除病原体能力的可用性。 目的1.确定CXCL10在炎症组织中塑造T细胞运动和功能中的作用 目的2.提高CXCL10的可获得性是否会影响T细胞的定位并增强对主要乳杆菌的免疫力？ 了解Th1在感染组织中的定位、运动和功能的基本线索可能是 对于开发适当增强对疫苗的适应性免疫反应的佐剂至关重要 并开发治疗方法，优化对慢性炎症的反应。

PROJECT SUMMARY/ABSTRACT Inflammatory cues within infected tissues are necessary for proper effector cell location and function. Spatial compartmentalization of T cells within lymph nodes (LNs) has recently been shown to promote T cell differentiation. Specifically, Th1 cell differentiation within LNs was shown to be dependent on CXCL10 (ligand for CXCR3, highly expressed on Th1 cells), as it served as a guiding cue for intra-nodal positioning and facilitated T cell:dendritic cell interactions during T cell priming. However, local cues that dictate effector T cell spatial location and function once T cells leave the LN and enter the tissue site of infection, are poorly understood. Using a reporter mouse for CXCL10 (REX3) and intra-vital multiphoton microscopy, we could, for the first time, determine the distribution of CXCL10 expressing cells at the site of inflammation in situ. We found a striking correlation between dense clusters of CXCL10 producers and the accumulation of Th1 cells. In addition, Th1 cells decelerated within the dense CXCL10-clusters. We hypothesize that the spatially restricted expression of CXCL10 is critical for the proper localization and function of Th1 cells within the inflamed/infected milieu. In many chronic infections, protective immunity is limited due to pathogen-induced modifications to the host micro-environment. Indeed, T cells have been shown to have limited access to dense areas of Leishmania major (L.major) and Toxoplasma Gondii infected cells in infected tissues. Our group previously showed that L.major can actively down regulate CXCL10 in infected macrophages, the predominant infected cell in the dermis. We hypothesize that by limiting CXCL10 expression in infected cells, L.major interferes with the proper localization and function of Th1 cells that are required for efficient pathogen clearance. The overall goal is to define basic mechanisms that influence Th1 positioning and/or function within specific micro-anatomical regions rich in CXCL10 in the inflamed milieu, and to determine the effect of CXCL10 availability on the ability of Th1 cells to locate and clear a pathogen. Aim 1. Determine the role of CXCL10 in shaping T cell motility and function within the inflamed tissue Aim 2. Can enhancing CXCL10 availability impact T cell positioning and boost immunity against L.major? Understanding the fundamental cues for Th1 localization, motility and function within infected tissues may be critical for the development of adjuvants that suitably enhance the adaptive immune response to vaccine antigens and to develop therapeutic approaches that optimize responses to chronic inflammation.