Remodeling of Lymph Node-Derived Cytokine Responses at the Infected Tissue Site

受感染组织部位淋巴结衍生细胞因子反应的重塑

• 批准号: 10271765
• 负责人: Deborah J Fowell
• 金额: $ 23.29万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271765
• 关键词: Anatomy; Antigens; Behavior; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CXCL9 gene; CXCR3 gene; Cell Communication; Cell Survival; Cells; Cues; Dermal; Dermis; Effector Cell; Enterobacteria phage P1 Cre recombinase; Environment; Event; Genes; Goals; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Interleukin-4; Knowledge; Lead; Leishmania major; Leukocytes; Ligands; Location; LoxP-flanked allele; Mediating; Molecular; Optics; Parasitic infection; Pathology; Pathway interactions; Phagocytes; Population; Positioning Attribute; RANTES; Reagent; Regulation; Scanning; Shapes; Signal Transduction; Site; System; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Time; Tissues; Up-Regulation; Vaccines; Work; adaptive immunity; antimicrobial; cell behavior; cell type; cellular targeting; chemokine; chronic infection; co-infection; cytokine; design; draining lymph node; effector T cell; insight; lymph nodes; multiphoton microscopy; new therapeutic target; pathogen; public health relevance; resistant strain; response; tool

 DESCRIPTION (provided by applicant): Intracellular pathogens modify their host environment to survive in infected cells and evade adaptive immunity. Fundamental to understanding host-pathogen interactions is the need to define how T cells accumulate and interact with infected cells fro pathogen clearance. In many chronic infections, the pathogen and host responses may work in concert to limit protective immunity. We have gained new insight into the early infected microenvironment that might shape the magnitude or efficiency of a local protective Th1 response to Leishmania major. L. major actively downregulates the expression of a number of Th1-associated chemokines, particularly the CXCR3 chemokines and establishes a non-protective IL-4-domintated immune response in both susceptible and resistant strains. IL-4 itself also negatively regulates Th1 chemokines (CXCL9-11, CCL5) in inflamed/infected dermal tissue, effectively compounding the pathogen hold on the chemokine milieu. We speculate that CXCR3-chemokine cues for micro-anatomical positioning maybe critical for optimal Th1 localization within infected tissues and robust pathogen clearance. The efficacy of Th1 function at the infection site will therefore depend on the availability of these positioning cues. Thus, we hypothesize that L. major and host IL-4 limit the expression of key chemokines required for Th1 cells to position and function within the infected milieu. The goal is to determine how the local modulation of CXCR3-chemokines by L. major and IL-4 shapes the developing Th1 response in the infected tissue. This is achieved using cutting-edge IV-MPM tools through the following aims: Specific Aim 1. Regulation of Th1 occupancy in the inflamed/infected dermis. Specific Aim 2. Regulation of Th1 positioning within inflamed/infected tissues. Specific Aim 3. Cellular targets of IL-4 in the regulation of CXCR3 ligand expression in inflamed tissue. This project will identify key pathways that promote or limit Th1 effector function within inflammatory sites. Defining the molecular events that impact effector T cell positioning in the tissues will be essential for the design of novel therapeutics that target chronic infection or co-infection by overriding the local tissue milieu.

 描述（由申请人提供）：细胞内病原体改变其宿主环境，以在感染细胞中存活并逃避适应性免疫。理解宿主-病原体相互作用的基础是需要定义T细胞如何积累并与感染细胞相互作用以清除病原体。在许多慢性感染中，病原体和宿主的反应可能会共同作用，限制保护性免疫。我们对早期感染的微环境有了新的认识，这可能会影响局部保护性Th 1对利什曼原虫的反应的程度或效率。L.主要主动下调许多Th 1相关趋化因子，特别是CXCR 3趋化因子的表达，并在易感和抗性菌株中建立非保护性IL-4主导的免疫应答。IL-4本身也负调节发炎/感染的皮肤组织中的Th 1趋化因子（CXCL 9 -11，CCL 5），有效地复合了趋化因子环境中的病原体。我们推测，CXCR 3-趋化因子线索的微观解剖定位可能是至关重要的最佳的Th 1感染组织内的定位和强大的病原体清除。因此，Th 1功能在感染部位的功效将取决于这些定位线索的可用性。因此我们 假设L.主要和宿主IL-4限制Th 1细胞在感染环境中定位和发挥功能所需的关键趋化因子的表达。我们的目标是确定L.主要和IL-4形状的发展中的Th 1反应在感染的组织。这是通过使用先进的IV-MPM工具，通过以下目标实现的：具体目标1.炎症/感染真皮中Th 1占据的调节。具体目标2。炎症/感染组织内Th 1定位的调节。具体目标3。细胞靶标 IL-4对炎症组织中CXCR 3配体表达的调节作用。该项目将确定 促进或限制炎症部位内Th 1效应子功能的关键途径。定义影响效应T细胞在组织中定位的分子事件对于通过覆盖局部组织环境来靶向慢性感染或合并感染的新型治疗剂的设计将是至关重要的。