Virus-induced Cell Fate Decisions in Anti-Viral Immunity

描述（如申请人所提供）：缺乏针对许多病毒的有效疫苗和治疗方法是一个重大的健康问题。宿主对病毒的防御需要由B细胞和T细胞提供的适应性免疫功能，但是控制这些细胞的功能和细胞命运决定的细胞和分子过程还不完全清楚。尽管病毒抗原的持久性、局部微环境中的细胞因子环境、淋巴和非淋巴器官中免疫细胞的浓度和位置以及共刺激的可用性和类型都可以显著影响对病毒感染或疫苗接种的免疫应答的最终生物学结果，目前还不清楚这些因素是如何控制的，也不清楚病毒是如何操纵这些因素中的每一个来逃避或破坏免疫力的。这些基本知识差距限制了我们合理设计新疫苗和开发治疗病毒介导疾病的干预措施的能力。因此，U19计划的总体目标是确定各种类型的病毒感染（慢性全身性、急性全身性和急性粘膜性）如何影响上述因素，并导致可能有益或病理性的特定类型的免疫应答。为了实现这一目标，在人类和小鼠抗病毒免疫学方面具有互补专业知识的五个实验室将合作解决抗病毒免疫中一些关键的未解决问题。在项目1中，UAB的Troy Randall将确定Tfh反应如何受IL-2信号传导和可用性控制。在项目2中，UAB的Allan Zajac将确定抗病毒CD 8 + T细胞反应如何由粘附分子和T细胞聚集控制。在项目3中，UAB的Frances隆德将确定IFN如何控制抗病毒B细胞反应？信令和可用性。在项目4中，加州大学戴维斯分校的Nicole Baumgarth将确定如何控制自然和诱导的抗病毒IgM反应。这些项目将由核心A -管理和生物统计学（Troy Randall）、核心B -病毒储备和试剂（Frances隆德）和核心C -人类免疫学（Frances Eun-Hyung Lee，Emory）促进。重要的是，所有项目将能够使用Core B开发的四聚体试剂检查病毒特异性B和T细胞。此外，虽然每个项目中的许多机制研究将使用小鼠模型进行，但这些项目还将通过与人类免疫学核心（Core C）的相互作用来测试人类的关键假设。

DESCRIPTION (as provided by applicant): The lack of effective vaccines and therapeutic treatments for many viruses presents a significant health concern. Host defenses against viruses require adaptive immune functions provided by both B cells and T cells, but the cellular and molecular processes that control the functions and cell fate decisions of these cells are incompletely understood. Although the persistence of viral antigens, the cytokine milieu in local microenvironments, the concentration and placement of immune cells in lymphoid and non-lymphoid organs, and the availability and type of co-stimulation can all dramatically affect the ultimate biological outcome of an immune response to virus infection or vaccination, it is unclear how these factors are controlled or how viruses manipulate each of these factors to evade or subvert immunity. These basic knowledge gaps limit our ability to rationally design new vaccines and develop interventions to treat virus-mediated diseases. Therefore the overall goal of this U19 Program is to determine how various types of virus infections (chronic-systemic, acute-systemic, and acute-mucosal) affect the factors described above and lead to specific types of immune responses that may be beneficial or pathologic. In order to meet this goal, five labs with complementary expertise in human and mouse antiviral immunology will work collaboratively to address some of these key unresolved issues in antiviral immunity. In Project 1, Troy Randall at UAB will determine how Tfh responses are controlled by IL-2 signaling and availability. In Project 2, Allan Zajac at UAB will determine how antiviral CD8+ T cells responses are controlled by adhesion molecules and T cell clustering. In Project 3, Frances Lund at UAB will determine how antiviral B cell responses are controlled by IFN? signaling and availability. In Project 4, Nicole Baumgarth of UC Davis will determine how natural and induced antiviral IgM responses are controlled. These projects will be facilitated by Core A - Administration and Biostatistics (Troy Randall), Core B - Viral Stocks and Reagents (Frances Lund), and Core C - Human Immunology (Frances Eun-Hyung Lee, Emory). Importantly, all projects will be able to examine virus-specific B and T cells using tetramer reagents developed by Core B. In addition, although many of the mechanistic studies in each project will be performed using mouse models, the projects will also test key hypotheses in humans via interactions with the Human Immunology Core (Core C).