Generation and Function of NK Cell Memory

NK细胞记忆的产生和功能

• 批准号: 8719937
• 负责人: ULRICH H VON ANDRIAN
• 金额: $ 83.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719937
• 关键词: AIDS/HIV problem; Acute; Address; Affinity; Anatomy; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Antiviral Agents; B-Cell Activation; B-Lymphocytes; Behavior; Binding; Biological Models; Blood Circulation; Blood Vessels; Blood flow; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Cells; Characteristics; Chronic; Clinical; Collaborations; Complement; Complement 3d Receptors; Complement Receptor; Consequences of HIV; Coupling; Data; Dendritic Cells; Deposition; Development; Disease; Drainage procedure; ERBB2 gene; Effectiveness; Event; Exposure to; Floor; Follicular Dendritic Cells; Functional disorder; Gatekeeping; Generations; HIV; HIV Antigens; HIV Infections; Helper-Inducer T-Lymphocyte; Hematopoietic; Host Defense; Human; Humoral Immunities; Image; Imagery; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin Class Switching; Immunologic Memory; Immunologist; Individual; Infection; Inflammatory; Influenza; Injection of therapeutic agent; Intervention; Investigation; Knowledge; Lead; Learning; Left; Life; Liquid substance; Lymph; Lymph Node Subcapsular Sinus; Lymphatic; Lymphatic System; Lymphocyte; Lymphocytic choriomeningitis virus; Mammals; Memory; Memory B-Lymphocyte; Microbe; Mind; Modeling; Monoclonal Antibodies; Mouse Strains; Mucous Membrane; Mus; Mutation; Myelogenous; Natural Immunity; Natural Killer Cells; Organ; Outcome; Pan Genus; Pathogenesis; Pathway interactions; Peripheral; Phagocytes; Phase; Phenotype; Physiological; Plant Roots; Play; Positioning Attribute; Prevention; Process; Proteins; Reaction; Receptor Signaling; Recording of previous events; Regulation; Relative (related person); Resistance; Reticular Cell; Role; Route; Series; Simplexvirus; Sinus; Site; Skin; Source; Stem cells; Stream; Streptococcus pneumoniae; Structure of germinal center of lymph node; Structure of subclavian vein; Surface; System; T cell response; T-Lymphocyte; Testing; Thoracic Duct; Time; Tissues; Travel; Vaccines; Vesicular stomatitis Indiana virus; Viral; Viral Antigens; Viral Vaccines; Virion; Virus; Virus Diseases; Work; adaptive immunity; antigen challenge; base; capsule; cell motility; complement pathway; complement system; cytokine; evidence base; exhaust; improved; in vivo; in vivo imaging; influenzavirus; insight; intravital microscopy; lymph nodes; macrophage; microbial; mouse model; multi-photon; nanoparticle; new therapeutic target; novel therapeutics; particle; pathogen; prevent; programs; prophylactic; receptor; research study; response; stem; tool; vaccine development

This Program entitled "Anti-viral Immune Responses in Lymph Nodes", seeks to gain a deeper understanding of the induction and regulation of immunological events that are elicited by viral antigens in lymph nodes (LNs). Many viruses and most conventional vaccines enter the body through the skin and travel via lymphatics to draining LNs. These organs are believed to have a critical role in the adaptive immune response to peripheral infections; therefore, understanding the cellular and molecular interactions that occur within LNs will provide insights that may be useful for improved vaccine development. Lymph-borne foreign matter entering LNs is captured and processed by antigen-presenting cells (APCs), which then present this material to B and T cells to elicit effector responses and long-lived immunological memory. The rules that determine how lymph-derived antigenic material is handled in LNs, especially in the context of ongoing infections, and what cells and molecules must interact to elicit a protective immune response (or fail to do so) are poorly understood. Why do some viruses (e.g. VSV in mice) induce a potent, multi-pronged protective immune response that eliminates the pathogen, while others (e.g. influenza) generate only transient protective immunity, and a few (e.g. HIV in humans) establish a chronic presence by continuously subverting and eventually exhausting the host's anti-viral defenses? The mechanisms behind these different outcomes are likely multi-factorial and depend upon differences in the way individual viruses interact with their hosts. To explore the dynamics of these interactions in living animals, all component projects of this Program will employ multi-photon intravital microscopy (MP-IVM) in intact LNs that will be offered in the Intravital Microscopy Core for time-and space-resolved visualization of the innate and adaptive immune response to lymph-borne virions. In Project 1, Dr. von Andrian will explore innate and adaptive immune responses to lymph-borne viral infections using VSV and several other viral pathogens. In Project 2. Drs. Sharpe and Wherry will visualize the effects of the negative costimulatory pathways, PD-1:PD-L1, PD-1:PD-L2 and PDL1 :B7.1 on antiviral immunity to influenza and LCMV. In Project 3. Dr. Carroll will dissect the role of complement and complement receptors in humoral immunity to influenza virus. Finally, in Project 4, Drs. Luster. Mempel and Taqer will characterize the cellular dynamics and viral dissemination in HIV-infected lymph nodes of humanized mice. It is hoped that the mechanistic insights gained from these highly interactive and synergistic experiments will lead to new, evidence-based and knowledge-driven development strategies for anti-viral vaccines.

该计划名为“淋巴结中的抗病毒免疫反应”，试图获得更深的 了解病毒抗原引起的免疫事件的诱导和调节 淋巴结（LNS）。许多病毒和大多数传统疫苗通过皮肤进入身体并行进 通过淋巴管来排干LN。据信这些器官在适应性免疫中起关键作用 对周围感染的反应；因此，了解发生的细胞和分子相互作用 在LN内，将提供可能有助于改善疫苗开发的见解。淋巴传播的外国 进入LNS的物质被抗原呈递细胞（APC）捕获并处理 对B和T细胞的材料，以引起效应子反应和长寿命的免疫记忆。规则 确定如何在LNS中处理淋巴衍生的抗原材料，尤其是在持续的情况下 感染以及哪些细胞和分子必须相互作用以引起保护性免疫反应（或不这样做） 知之甚少。为什么一些病毒（例如，小鼠中的VSV）引起有效的多管齐下保护 消除病原体的免疫反应，而其他人（例如流感）仅产生瞬态 保护性免疫，一些（例如，人类的艾滋病毒）通过不断颠覆建立慢性存在 并最终用尽宿主的抗病毒防御？这些不同结果背后的机制 可能是多因素的，并且取决于单个病毒与宿主相互作用的方式的差异。 为了探索活动物中这些相互作用的动态，该计划的所有组成项目都将 在完整的LNS中采用多光子插入式显微镜（MP-IVM） 显微镜核心，用于天生的时间和空间可视化对先天性和适应性免疫反应的可视化 淋巴传播病毒体。在项目1中，冯·安德里安（Von Andrian）博士将探讨对天赋和适应性免疫反应 使用VSV和其他几种病毒病原体，淋巴传播的病毒感染。在项目2中。夏普和 Wherry将可视化负共刺激途径的影响PD-1：PD-L1，PD-1：PD-L2和PDL1 ：B7.1对抗病毒对流感和LCMV的免疫力。在项目3中。卡洛尔博士将剖析 对流感病毒的体液免疫的补体和补体受体。最后，在项目4中，博士。 光泽。 Mempel和Taqer将表征HIV感染的细胞动力学和病毒传播 人性化小鼠的淋巴结。希望从这些方面获得的机械见解很高 互动和协同实验将导致新的，循证的和知识驱动的发展 抗病毒疫苗的策略。