CD4 T cells in anti-viral immunity and immune pathology

CD4 T 细胞在抗病毒免疫和免疫病理学中的作用

• 批准号: 8652531
• 负责人: Raymond M Welsh
• 金额: $ 236.85万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652531
• 关键词: Address; Affinity; Antibody Formation; Antigen Presentation; Area; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cloning; Collaborations; Communication; Complex; Consultations; Effector Cell; Epitopes; Generations; Goals; HIV Infections; Human; Human Herpesvirus 6; Immune; Immune response; Immune system; Immunity; Immunologist; Immunology; Infection; Influenza; Influenza A virus; Joints; Knowledge; Laboratories; Lesion; Lung; Lymphocytic choriomeningitis virus; MHC Class II Genes; Massachusetts; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular; Natural Immunity; Natural Killer Cells; Pathogenesis; Pathology; Peptide/MHC Complex; Property; Reagent; Regulation; Research; Research Personnel; Research Project Grants; Resource Sharing; Respiratory Tract Infections; Rest; Role; Route; Scientist; Structure; System; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; Therapeutic; Transgenic Mice; Transgenic Organisms; Translating; United States National Institutes of Health; Universities; Vaccine Design; Vaccines; Vaccinia virus; Viral; Viral Pathogenesis; Virus; Virus Diseases; Work; adaptive immunity; combat; cross reactivity; data management; design; immunopathology; influenzavirus; insight; interest; medical schools; meetings; memory CD4 T lymphocyte; mouse model; mucosal site; new technology; pathogen; programs; prophylactic; respiratory; response; stem; technology development

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.

描述（由申请人提供）：长期以来，CD4 T细胞一直被认为是其余免疫系统的编排者，但是CD4 T细胞研究的过去十年揭示了许多新功能和CD4 T细胞的新功能和新的子集，因此需要检查这些子集与其他免疫系统之间的相互作用。我们在这里提出了一个协作U19计划，以响应RFA-AI-12-048，即病毒控制的免疫机制。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和适应性免疫机制之间的相互作用，（2）在肺部肺部检查此类作用，在这种情况下，在这种情况下，（3）检查感染后的T和B细胞群在感染后保持不同的T和B细胞群如何维持多种失败的影响，并定义了多种感染的影响。该U19研究了该RFA感兴趣的病毒，包括第1组（HHV-6），第3A组（LCMV，Vaccinia病毒）和3C组（流感病毒）病原体。此外，我们的程序使用的小鼠模型提供了有关对病毒感染的免疫反应的有价值信息，并将这些发现转化为人类免疫学。该计划由雷蒙德·威尔士（Raymond Welsh）博士指导，涉及马萨诸塞大学医学院（UMMS）的一个系（病理）中的科学家。它由四个研究项目，一个行政核心和两个科学核心组成，它们将为项目提供试剂以及追求新颖的技术开发。项目1（威尔士博士）研究了NK细胞充当CD4 T细胞自然抑制因子并调节B细胞的能力以及肺中CD8 T细胞依赖性病理和持久性的能力。项目2（Swain博士）研究了记忆CD4 T细胞如何改变先天性和适应性免疫，以使流感病毒并有助于长期抗体反应；项目3（Selin博士）研究了不同病毒之间的CD4和CD8 T细胞如何在小鼠模型和人类流感受试者中介导肺中有害异源免疫的交叉反应；项目4（Stern博士）研究了人类HHV-6特异性CD4 T细胞反应如何调节并由CD8细胞和NK细胞调节。这些高度协作的项目将依靠核心B（Stern博士），该项目将提供用于T细胞分析的MHC试剂，以及核心C（Huseby博士），该试剂将提供T细胞受体克隆和转基因小鼠。该计划将由行政核心A（威尔士博士）协调，该计划将安排会议，咨询，资源共享，并提供统计分析和数据管理。这项工作应提供有关如何最好地利用这些特性在疫苗策略设计中的见解。 相关性：呼吸道的感染是人类疾病的主要原因之一，它们可能是由许多不同的病毒引起的，这些病毒引起了强烈的免疫反应和免疫病理病变。该程序项目研究了CD4 T细胞如何考虑免疫系统的编排，与B细胞，CD8 T细胞，NK细胞和先天免疫系统相互作用，以介导或排除病毒诱导的免疫病理学。该研究获得的知识应有助于建造疫苗和呼吸道感染的治疗方法。