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

 描述(申请人提供)：细胞内病原体改变它们的宿主环境以在受感染的细胞中生存并逃避适应性免疫。了解宿主-病原体相互作用的基础是需要确定T细胞如何积聚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协同作用，限制保护性免疫。我们对早期感染的微环境有了新的认识，这种微环境可能会影响局部保护性Th1反应的大小或效率。主要通过主动下调Th1相关趋化因子，特别是CXCR3趋化因子的表达，在敏感株和耐药株中建立非保护性的IL-4主导的免疫反应。IL-4本身也对炎症/感染的皮肤组织中的Th1趋化因子(CXCL9-11，CCL5)进行负面调节，有效地复合了病原体对趋化因子环境的控制。我们推测，用于显微解剖定位的CXCR3趋化因子提示可能对Th1在感染组织中的最佳定位和强大的病原体清除至关重要。因此，Th1功能在感染部位的有效性将取决于这些定位线索的可用性。因此，我们 假设梅杰乳杆菌和宿主IL-4限制了Th1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。研究的目的是确定梅杰乳杆菌和IL-4对CXCR3趋化因子的局部调节如何塑造感染组织中发育中的Th1反应。这是通过使用尖端的IV-MPM工具通过以下目标实现的：具体目标1。调节炎症/感染真皮中Th1的占位。特定目的2.炎症/感染组织中Th1定位的调节。特定目标3.细胞靶标 IL-4在炎症组织CXCR3配体表达调控中的作用该项目将确定 在炎症部位促进或限制Th1效应器功能的关键途径。确定影响效应器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针对慢性感染或混合感染的新疗法的设计至关重要。

 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.