Generation and Function of NK Cell Memory

该计划题为“抗病毒免疫反应在淋巴结”，旨在获得更深层次的 理解病毒抗原引起的免疫事件的诱导和调节， 淋巴结（LN）。许多病毒和大多数常规疫苗通过皮肤进入人体并传播 通过反渗透系统排出淋巴结这些器官被认为在适应性免疫中起关键作用。 对外周感染的反应;因此，了解发生的细胞和分子相互作用， 将提供可能对改进疫苗开发有用的见解。淋巴源性异物 进入淋巴结的物质被抗原呈递细胞（APC）捕获和处理，然后APC将其呈递给淋巴结。 材料至B和T细胞以引发效应子应答和长期免疫记忆。的规则 确定淋巴细胞来源的抗原物质如何在淋巴结中处理，特别是在正在进行的 感染，以及哪些细胞和分子必须相互作用以引发保护性免疫反应（或未能这样做） 我们对此知之甚少。为什么某些病毒（例如小鼠中的VSV）会诱导有效的、多管齐下的保护作用 消除病原体的免疫反应，而其他免疫反应（如流感）仅产生短暂的 保护性免疫，少数（例如人类的HIV）通过持续破坏 最终耗尽宿主的抗病毒防御能力这些不同结果背后的机制 可能是多因素的，并取决于不同的病毒与其宿主相互作用的方式。 为了探索活体动物中这些相互作用的动态，本计划的所有组成项目将 在完整LN中采用多光子活体显微镜（MP-IVM），该显微镜将在活体中提供 显微镜核心用于先天性和适应性免疫反应的时间和空间分辨可视化， 淋巴传播的病毒体。在项目1中，冯安德里安博士将探索先天性和适应性免疫反应， 使用VSV和其他几种病毒病原体的淋巴传播病毒感染。在项目2中。夏普医生和 Wherry将可视化负共刺激通路PD-1：PD-L1、PD-1：PD-L2和PDL 1的作用 ：B7.1对流感和LCMV的抗病毒免疫。在项目3中。卡罗尔博士将剖析 补体和补体受体在流感病毒体液免疫中的作用。最后，在项目4中，博士。 辉煌不再. Mempel和Taqer将描述HIV感染者中的细胞动力学和病毒传播。 人源化小鼠的淋巴结。人们希望，从这些高度机械化的见解， 互动和协同实验将导致新的、基于证据和知识驱动的发展 抗病毒疫苗的策略。

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.