Anti-viral immune responses in lymph node

描述（由申请人提供）：本项目题为“淋巴结中的抗病毒免疫反应”，旨在更深入地了解淋巴结（LN）中病毒抗原引起的免疫事件的诱导和调节。许多病毒和大多数常规疫苗通过皮肤进入人体，并通过毛细血管进入淋巴结。这些器官被认为在对外周感染的适应性免疫应答中具有关键作用;因此，了解LN内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。进入LN的淋巴携带的异物被抗原呈递细胞（APC）捕获和处理，然后抗原呈递细胞（APC）将该物质呈递给B和T细胞以引发效应器应答和长期免疫记忆。决定淋巴细胞来源的抗原物质在淋巴结中如何处理的规则，特别是在持续感染的情况下，以及哪些细胞和分子必须相互作用以引发保护性免疫应答（或不能这样做）的规则知之甚少。为什么有些病毒（例如小鼠中的VSV）诱导一种强有力的、多管齐下的保护性免疫反应，从而消除病原体，而另一些病毒（例如流感）只产生短暂的保护性免疫，而少数病毒（例如人类中的HIV）通过持续破坏并最终耗尽宿主的抗病毒防御来建立长期存在？这些不同结果背后的机制可能是多因素的，并取决于个体病毒与宿主相互作用的方式差异。为了探索活体动物中这些相互作用的动态，该计划的所有组成项目将在完整的LN中采用多光子活体显微镜（MP-IVM），该显微镜将在活体显微镜核心中提供，用于对淋巴传播病毒粒子的先天性和适应性免疫反应的时间和空间分辨可视化。在项目1中，von Andrian博士将利用VSV和其他几种病毒病原体探索对淋巴传播病毒感染的先天性和适应性免疫反应。在项目2中。Sharpe和Wherry博士将可视化负共刺激通路PD-1：PD-L1、PD-1：PD-L2和PDL 1：B7.1对流感和LCMV抗病毒免疫的影响。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，Luster博士。Mempel和Tager将表征人源化小鼠HIV感染淋巴结中的细胞动力学和病毒传播。希望从这些高度互动和协同的实验中获得的机制见解将导致新的，基于证据和知识驱动的抗病毒疫苗开发策略。

DESCRIPTION (provided by applicant): 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 Tager 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.