CD4 T cells in anti-viral immunity and immune pathology

描述（由申请人提供）：CD4 T细胞长期以来被认为是免疫系统其余部分的协调者，但过去十年的CD4 T细胞研究揭示了许多新的功能和CD4 T细胞的新亚群，因此这些亚群与免疫系统其余部分之间在病毒发病机制方面的相互作用需要进行研究。根据RFA-AI-12-048《病毒控制的免疫机制》，我们在此提出一个合作的U19项目。提出的工作与RFA的目标高度一致，包括(1)检查病毒系统中先天免疫和适应性免疫机制之间的相互作用，(2)检查粘膜部位的这种作用，在这种情况下是肺，(3)检查感染后不同的T细胞和B细胞亚群是如何维持的，以及(4)定义多重感染对病毒免疫和发病机制的影响。该U19研究RFA感兴趣的病毒，包括1组（HHV-6）， 3A组（LCMV，牛痘病毒）和3C组（流感病毒）病原体。此外，我们的项目使用了小鼠模型，这些模型提供了有关病毒感染免疫反应的宝贵信息，并将这些发现转化为人类免疫学。该项目由雷蒙德·威尔士博士指导，涉及马萨诸塞大学医学院（UMMS）一个部门（病理学）的合作科学家。它包括四个研究项目，一个行政核心和两个科学核心，将为项目提供试剂并追求新技术开发。项目1 （Dr. Welsh）检测NK细胞作为CD4 T细胞的天然抑制因子，调节B细胞和CD8 T细胞依赖性病理和肺持久性的能力；项目2 （Swain博士）研究记忆性CD4 T细胞如何改变对甲型流感病毒的先天和适应性免疫，并促进长期抗体反应；项目3 （Selin博士）研究不同病毒之间的CD4和CD8 T细胞交叉反应如何在小鼠模型和人类流感受试者的肺部介导有害的异源免疫；Project 4 （Dr. Stern）研究人类hhv -6特异性CD4 T细胞反应是如何被CD8细胞和NK细胞调节的。这些高度合作的项目将依赖于核心B （Stern博士）和核心C （Huseby博士），前者将提供用于T细胞分析的MHC试剂，后者将提供T细胞受体克隆和转基因小鼠。该计划将由行政核心A （Welsh博士）协调，负责安排会议、磋商、资源共享，并提供统计分析和数据管理。这项工作应该为如何在疫苗策略的设计中最好地利用这些特性提供见解。

DESCRIPTION (provided by applicant): CD4 T cells have long been thought to be orchestrators of the rest of the immune system, but the past decade of CD4 T cell research has revealed many new functions and new subsets of CD4 T cells such that the interactions between these subsets and the rest of the immune system in regards to viral pathogenesis need to be examined. We propose here a collaborative U19 program in response to RFA-AI-12-048, Immune Mechanisms of Virus Control. The work proposed is highly consistent with the aims of the RFA, including (1) examining the interactions between innate and adaptive immune mechanisms in viral systems, (2) examining such actions at mucosal sites, in this case the lung, (3) examining how different T and B cell subsets are maintained after infection, and (4) defining the impact of multiple infections on viral immunity and pathogenesis. This U19 studies viruses of interest to this RFA, including Group 1 (HHV-6), Group 3A (LCMV, vaccinia virus), and Group 3C (influenza virus) pathogens. Further, our program uses mouse models that have provided valuable information regarding the immune response to viral infections, and it translates these findings into human immunology. This program is directed by Dr. Raymond Welsh and involves already collaborating scientists within one department (Pathology) at the University of Massachusetts Medical School (UMMS). It consists of four research projects, one administrative core, and two scientific cores that will provide reagents to the projects as well as pursue novel technology development. Project 1 (Dr. Welsh) examines the ability of NK cells to act as natural suppressors of CD4 T cells and regulate B cells and CD8 T cell-dependent pathology and persistence in the lung; Project 2 (Dr. Swain) examines how memory CD4 T cells alter both innate and adaptive immunity to influenza A virus and contribute to long term antibody responses; Project 3 (Dr. Selin) examines how CD4 and CD8 T cells cross-reactive between different viruses mediate detrimental heterologous immunity in the lung in mouse models and in human influenza subjects; Project 4 (Dr. Stern) examines how human HHV-6-specific CD4 T cell responses regulate and are regulated by CD8 cells and NK cells. These highly collaborative projects will rely on a core B (Dr. Stern), which will provide MHC reagents for T cell analyses, and a core C (Dr. Huseby), which will provide T cell receptor cloning and transgenic mice. This program will be coordinated by an administrative Core A (Dr. Welsh), which will arrange meetings, consultations, resource sharing, and provide statistical analysis and data management. This work should provide insights into how to best harness these properties in the design of vaccine strategies. RELEVANCE: Infections of the respiratory track are among the leading cause of human illnesses, and they can be caused by many different viruses, which elicit strong immune responses and immunopathological lesions. This program project examines how CD4 T cells, considered the orchestrators of the immune system, interact with B cells, CD8 T cells, NK cells and the innate immune system to mediate or preclude virus-induced immunopathology. Knowledge gained form this study should help in the construction of vaccines and treatments for respiratory infections.