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

描述(由申请人提供)：这份U19申请的多研究人员计划检查病毒控制的免疫机制，重点是CD8效应T细胞在协调病毒清除和控制与宿主对病毒感染的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支持性科学核心构成了方案。这些项目旨在探索先天免疫细胞(特别是自然杀伤(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细胞可以有效地清除病毒/病毒感染的细胞，并控制与不同感染部位的T细胞识别病毒相关的过度和潜在的破坏性炎症。该计划的具体目标实现了RFA规定的几个目标，包括了解和定义先天性免疫细胞在调节不同病毒感染部位的适应性反应中的作用。本程序还研究了与有效清除病毒同样重要的一个主题，即组织炎症和损伤的控制，并探索了效应器CD8T细胞(即来自L-10的效应器T细胞和由效应器T细胞抑制的NK受体表达)对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和互补性技能的项目负责人。个别项目负责人和核心主管既有先前的合作，也有持续的合作。在这个项目中，我们提出了以下问题：1、抗病毒CD8T细胞产生的白介素10(IL-10)是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的，是什么因素控制了效应T细胞产生这种调节细胞因子(项目1)；2.CD8T细胞对嗜肝病毒感染和适应性免疫诱导的缺陷是什么？肝脏NK细胞(和肝脏树突状细胞与NK细胞的相互作用)如何调节CD8T细胞反应的大小和质量(项目2)；3.NK细胞如何控制次级淋巴器官(即脾)感染部位的早期病毒复制，以及NK细胞的激活状态，如何影响病毒清除以及抗病毒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受体NKG2A表达的因素是什么，以及这种抑制受体的参与如何控制病毒感染的肺部的过度炎症和抑制免疫病理(项目4)？ 项目1：白介素10与急性呼吸道病毒感染(Braciale，T) 项目1说明(由申请人提供)：肺部炎症和损伤是呼吸道病毒感染的常见结果(在某些情况下是致命的)。呼吸道病毒感染触发宿主先天免疫系统和获得性免疫系统的协调反应。宿主反应对病毒清除和恢复至关重要，但也是伴随病毒清除而导致肺损伤的重要原因。最近的相关例子是在人类感染SARS冠状病毒和H5N1禽流感病毒时观察到的免疫介导的肺部炎症/损伤。项目1的长期目标是确定和表征先天免疫系统的细胞，即树突状细胞、单核/巨噬细胞、NK细胞和获得性免疫效应T淋巴细胞(Te)在病毒清除过程中和在实验性病毒感染期间控制炎症/损伤过程中的相互作用。 这一应用的基础是我们最近在A型流感小鼠感染模型中意想不到的发现：在Te对感染和病毒清除的反应中，抗病毒效应T细胞(包括CD4Te和更突出的CD8Te)渗透到受感染的肺中，产生高水平的抗炎/调节细胞因子IL-10。此外，我们还发现，在感染过程中阻断Te来源的IL-10的作用会导致肺部炎症和致命性损伤的增加。我们的证据进一步表明，这种源于Te的IL-10在控制单个核细胞因病毒感染而渗入感染肺所产生的肺部炎症/损伤水平以及病毒免疫(Te)释放的促炎介质方面发挥核心作用。我们希望分析IL-10，特别是Te来源的IL-10在感染肺中的表达和调节，以及这种细胞因子在控制病毒清除和肺部炎症/损伤中的作用。项目1的目的是：1.评估IL-10在流感病毒感染中的细胞来源和作用；2.分析流感感染过程中Te对IL-10产生的调节；3.确定病毒感染对Te衍生的IL-10产生的影响。建议的研究旨在补充项目2、3和4中正在进行的相关研究。

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.