Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection

描述（由申请人提供）：这是一份U19申请，旨在研究病毒控制的免疫机制，主要研究CD8 +效应t细胞在协调病毒清除和控制与宿主对病毒感染反应相关的组织炎症和损伤中的作用。四个高度互动和协同的项目和两个配套的科学核心组成了该计划。这些项目旨在探索先天免疫细胞（特别是自然杀伤细胞（NK）细胞和树突状细胞/巨噬细胞）及其产物在调节效应CD8 + T细胞发育中的作用，CD8 + T细胞可以有效地消除病毒/病毒感染的细胞，并控制与T细胞识别不同感染部位的病毒相关的过量和潜在的有害炎症。该计划的具体目标实现了RFA的几个既定目标，包括理解和定义先天免疫细胞在调节病毒感染不同部位的适应性反应中的作用。该计划还涉及与有效病毒清除一样重要的主题，即组织炎症和损伤的控制，并探索效应CD8 + T细胞（即效应T细胞衍生的I -10和效应T细胞抑制NK受体表达）所表现出的组织炎症和损伤控制的内在机制的贡献。该计划汇集了在病毒免疫学、哺乳动物遗传学、病毒学和临床医学领域具有独特专业知识和多样化互补技能的项目领导者。个别项目负责人和核心总监都有之前和正在进行的合作。在这个项目中，我们提出了以下问题：抗病毒CD8 +效应t细胞产生的I -10（白细胞介素-10）如何影响急性呼吸道病毒感染的病毒清除和控制肺部炎症，以及哪些因素控制效应t细胞产生这种调节性细胞因子（项目1）？2. CD8 + T细胞效应对嗜肝病毒感染和肝脏适应性免疫诱导反应缺陷的本质是什么？肝NK细胞（和肝树突状细胞-NK细胞相互作用）如何调节CD8 + T细胞反应的大小和质量（项目2）7；3. NK细胞介导的在次级淋巴器官（即脾脏）感染部位的早期病毒复制的控制，以及NK细胞的激活状态，如何影响病毒消除以及抗病毒CD8 + T细胞反应的速度和质量（项目3）？4. 控制CD8 +效应T细胞上抑制性nk型受体NKG2A表达的因素是什么？这种抑制性受体的参与如何控制病毒感染肺部的过度炎症和抑制免疫病理（项目4）？

DESCRIPTION (provided by applicant): This U19 application for a Multi-Investigator Program to examine Immune Mechanisms of Virus Control focuses on the role of CD8 + effector T-cells in orchestrating clearance of virus and in the control of tissue inflammation and injury associated with the host response to virus infection. Four highly interactive and synergistic Projects and two supporting scientific cores comprise program. These projects are designed to explore the role of innate immune cells (notably natural killer (NK) cells and dendritic cell/macrophages) and their products in regulating the development of effector CD8 + T cells which can efficiently eliminates virus/virus infected cells and control excess and potentially injurious inflammation associated with T cell recognition of viruses at different sites of infection. The Specific Aims of the Program fulfill several of the stated Aims of the RFA including understanding and defining the role of innate immune cells in regulating adaptive responses at different sites of virus infection.' This Program also deals with a topic as important as effective virus clearance that is the control of tissue inflammation and injury and explores the contribution of intrinsic mechanisms of control of tissue inflammation and injury exhibited by effector CD8 + T cells (i.e. effector T cell derived I L-10 and inhibitory NK receptor expression by the effector T cells). The Program brings together project leaders with unique expertise and diverse and complementary skills in the areas of Viral Immunology, Mammalian Genetics, Virology and Clinical Medicine. The individual Project Leaders and Core Directors have both prior and ongoing collaborations. In this program we proposed to examine the following questions: How does I L-10 (interleukin-10) produced by antiviral CD8 + effector T-cells affect virus clearance and control lung inflammation in acute respiratory virus infection and what factors control the production of this regulatory cytokine by effector T-cells (Project 1)?; 2. What is the nature of the defect in the CD8 + T-cell effector response to hepatotropic virus infection and adaptive immune induction in the liver and how do liver NK cells (and liver dendritic cell-NK cell interactions) regulate the magnitude and the quality of the CD8 + T cell response (Project 2)7; 3. How does NK cell mediated control of early virus replication at the site of infection in a secondary lymphoid organ i.e. the spleen, and the activation state of the NK cells, affect virus elimination and the tempo and quality of the antiviral CD8 + T cell response (Project 3)?; 4. What are the factors that control the expression of an inhibitory NK-type receptor NKG2A on CD8 + effector T cells and how does that engagement of this inhibitory receptor control excess Inflammation and inhibit immune pathology in the virus infected lungs (Project 4)? PROJECT 1: lnterleukin-10 in acute respiratory virus infection (Braciale, T) PROJECT 1 DESCRIPTION (provided by applicant): Pulmonary inflammation and injury is a frequent (and, in some instances, lethal) outcome of virus infections of the respiratory tract. Respiratory virus infection triggers a coordinated response from the host innate and adaptive immune systems. The host response is essential for virus clearance and recovery, but is also a significant cause of pulmonary injury that can accompany virus elimination. Relevant recent examples of this are the immune-mediated lung inflammation/injury observed in human infections with the SARS coronavirus and the H5N1 avian influenza viruses. The long-term goal of Project 1 is to define and characterize the interactions between cells of the innate immune system i.e. dendritic cells, monocyte/ macrophage, NK cells and adaptive immune effector T lymphocytes (Te) in the process of virus clearance and in the control of inflammation/injury during experimental virus infection of the respiratory tract. The foundation for this application is our recent and unexpected findings in the murine model of type A influenza infection that anti-viral effector T-cells (both CD4 +Te and more prominently CD8 +Te) infiltrating the infected lungs produce high levels of the anti-inflammatory/regulatory cytokines IL-10 during the Te response to infection and virus elimination. Furthermore, we found that blocking the effect of Te-derived IL- 10 during infection results in increased pulmonary inflammation and lethal injury. Our evidence further suggests that this Te-derived IL-10 plays a central role in controlling the level of lung inflammation/injury produced by mononuclear cells infiltrating the infected lungs in response to virus infection and the proinflammatory mediators released by virus- immune (Te). We wish to analyze the expression and regulation of IL-10 and specifically Te-derived IL-10 in the infected lungs and the impact of this cytokine on the control of virus clearance and lung inflammation/injury. The aims of Project 1 are: 1. To evaluate the cellular sources and effects of IL-10 on influenza virus infection; 2. To analyze the regulation of IL-10 production by Te during influenza infection; 3. To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4.