CD4 T cells in anti-viral immunity and immune pathology

描述（由申请人提供）：长期以来，CD 4 T细胞一直被认为是免疫系统其余部分的协调者，但过去十年的CD 4 T细胞研究揭示了CD 4 T细胞的许多新功能和新亚群，因此需要检查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。我们在此提出了一项U19合作计划，以响应RFA-AI-12-048《病毒控制的免疫机制》。所提出的工作与RFA的目的高度一致，包括（1）检查病毒系统中先天性和适应性免疫机制之间的相互作用，（2）检查粘膜部位（本例中为肺）的此类作用，（3）检查感染后如何维持不同的T和B细胞亚群，以及（4）定义多重感染对病毒免疫和发病机制的影响。本U19研究了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有价值的信息，并将这些发现转化为人类免疫学。该计划由Raymond Welsh博士指导，并涉及马萨诸塞州医学院（UMMS）一个部门（病理学）内的合作科学家。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，并追求新的技术开发。项目1（Welsh博士）检查NK细胞作为CD 4 T细胞的天然抑制因子并调节B细胞和CD 8 T细胞依赖性病理学的能力以及在肺中的持久性;项目2（Swain博士）研究了记忆CD 4 T细胞如何改变对甲型流感病毒的先天免疫和适应性免疫，并有助于长期抗体应答;项目3（Selin博士）研究了不同病毒之间的CD 4和CD 8 T细胞交叉反应如何介导小鼠模型和人类流感受试者肺中有害的异源免疫;项目4（Stern博士）研究了人类HHV-6特异性CD 4 T细胞应答如何调节以及受CD 8细胞和NK细胞调节。这些高度合作的项目将依赖于一个核心B（Stern博士），它将提供用于T细胞分析的MHC试剂，以及一个核心C（Huseby博士），它将提供T细胞受体克隆和转基因小鼠。该计划将由一个行政核心A（威尔士博士）协调，该核心A将安排会议，咨询，资源共享，并提供统计分析和数据管理。这项工作应该提供洞察如何最好地利用这些特性在疫苗策略的设计。 相关性：呼吸道感染是人类疾病的主要原因之一，它们可以由许多不同的病毒引起，这些病毒引起强烈的免疫反应和免疫病理学病变。该计划项目研究了CD 4 T细胞，被认为是免疫系统的管弦乐队，如何与B细胞，CD 8 T细胞，NK细胞和先天免疫系统相互作用，以介导或阻止病毒诱导的免疫病理学。从这项研究中获得的知识应该有助于呼吸道感染的疫苗和治疗方法的构建。

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.