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

焦点CXCL10在塑造炎症皮肤Th1微定位和功能中的作用

• 批准号: 9610313
• 负责人: Hen Prizant
• 金额: $ 5.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9610313
• 关键词: Acute; Address; Adjuvant; Anatomy; Antigen-Presenting Cells; Antigens; Area; Binding; Biological; CXCL10 gene; CXCR3 gene; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Chronic; Computer Analysis; Cues; Cutaneous; Dendritic Cells; Dermis; Development; Ear; Effector Cell; Equilibrium; Exertion; Flow Cytometry; Fluorescent Antibody Technique; Goals; Immunity; Immunize; In Situ; Infection; Inflammation; Inflammatory; Interferons; Interleukin-4; Label; Leishmania major; Ligands; Light; Location; Microscopy; Modification; Movement; Mus; Nodal; Parasite Control; Pattern; Peptide/MHC Complex; Peripheral; Positioning Attribute; Production; Reporter; Role; Shapes; Signal Transduction; Site; Skin; Stains; System; T cell differentiation; T-Cell Activation; T-Lymphocyte; Th1 Cells; Th2 Cells; Therapeutic; Time; Tissues; Toxoplasma gondii; Up-Regulation; Vaccine Antigen; Vaccines; Viral Tumor Antigens; adaptive immune response; adaptive immunity; cell behavior; cell motility; chemokine; chemokine receptor; chronic infection; cytokine; lymph nodes; macrophage; novel; pathogen; photoactivation; recruit; response; tool

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.

项目概要/摘要 受感染组织内的炎症信号对于效应细胞的正确定位和功能是必要的。空间 最近显示，淋巴结 (LN) 内 T 细胞的区室化可以促进 T 细胞的生长 差异化。具体而言，LN 内的 Th1 细胞分化被证明依赖于 CXCL10（配体 CXCR3，在 Th1 细胞上高度表达），因为它作为结内定位的指导线索并促进 T 细胞：T 细胞启动过程中树突状细胞的相互作用。然而，决定效应 T 细胞空间的局部线索 人们对 T 细胞离开淋巴结并进入感染组织部位后的位置和功能知之甚少。 使用 CXCL10 (REX3) 报告小鼠和活体多光子显微镜，我们第一次可以 确定 CXCL10 表达细胞在炎症部位的原位分布。我们发现了一个引人注目的 CXCL10 生产者密集簇与 Th1 细胞积累之间的相关性。此外，Th1 细胞在密集的 CXCL10 簇内减速。我们假设空间限制表达 CXCL10 对于 Th1 细胞在发炎/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，由于病原体诱导的宿主改变，保护性免疫受到限制 微观环境。事实上，T 细胞已被证明进入大型利什曼原虫密集区域的能力有限。 (L.major) 和弓形虫感染组织中的细胞。我们小组之前表明 L.major 可以主动下调受感染巨噬细胞（真皮中主要的受感染细胞）中的 CXCL10。我们 假设通过限制受感染细胞中的 CXCL10 表达，L.major 会干扰正确的定位 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特定范围内 Th1 定位和/或功能的基本机制。 发炎环境中富含 CXCL10 的显微解剖区域，并确定 CXCL10 的作用 Th1 细胞定位和清除病原体的能力的可用性。 目标 1. 确定 CXCL10 在塑造炎症组织内 T 细胞运动和功能中的作用 目标 2. 增强 CXCL10 可用性能否影响 T 细胞定位并增强对 L.major 的免疫力？ 了解受感染组织内 Th1 定位、运动和功能的基本线索可能是 对于开发适当增强疫苗适应性免疫反应的佐剂至关重要 抗原并开发优化慢性炎症反应的治疗方法。