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: 9443502
• 负责人: Raymond M Welsh
• 金额: $ 237.52万
• 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/9443502
• 关键词: Address; Affinity; Antibody Formation; Antibody Response; Antigen Presentation; Area; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cloning; Collaborations; Communication; Complex; Consultations; Development; Effector Cell; Epitopes; Generations; Goals; HIV Infections; Histocompatibility Antigens Class II; Human; Human Herpesvirus 6; Immune; Immune response; Immune system; Immunity; Immunologist; Immunology; Infection; Influenza; Influenza A virus; Innate Immune System; Joints; Knowledge; Laboratories; Lesion; Lung; Lymphocytic choriomeningitis virus; 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; Statistical Data Interpretation; 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; Viral Respiratory Tract Infection; Virus; Virus Diseases; Work; adaptive immunity; antiviral 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; synergism; 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 CD4 T 细胞的许多新功能和新亚群，使得相互作用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差异。我们在此提出一项 U19 协作计划，以响应 RFA-AI-12-048“病毒控制的免疫机制”。拟议的工作与 RFA 的目标高度一致，包括（1）检查病毒系统中先天性免疫机制和适应性免疫机制之间的相互作用，（2）检查粘膜部位（在本例中为肺）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。该 U19 研究本 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，我们的项目使用的小鼠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 Raymond Welsh 博士指导，涉及马萨诸塞大学医学院 (UMMS) 一个系（病理学）内的合作科学家。它由四个研究项目、一个行政核心和两个科学核心组成，将为项目提供试剂并追求新技术开发。项目 1（Welsh 博士）检查 NK 细胞作为 CD4 T 细胞的天然抑制因子并调节 B 细胞和 CD8 T 细胞依赖性病理学和肺部持久性的能力；项目 2（Swain 博士）研究记忆 CD4 T 细胞如何改变对甲型流感病毒的先天性和适应性免疫并促进长期抗体反应；项目 3（Selin 博士）研究 CD4 和 CD8 T 细胞在不同病毒之间的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；项目 4（Stern 博士）研究人类 HHV-6 特异性 CD4 T 细胞反应如何调节以及如何受 CD8 细胞和 NK 细胞调节。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（威尔士博士）负责协调，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设计中最好地利用这些特性提供见解。 相关性：呼吸道感染是人类疾病的主要原因之一，可由许多不同的病毒引起，这些病毒会引起强烈的免疫反应和免疫病理学病变。该项目研究 CD4 T 细胞（被认为是免疫系统的协调者）如何与 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。从这项研究中获得的知识应该有助于开发呼吸道感染的疫苗和治疗方法。

项目成果

Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy.

• DOI: 10.3389/fimmu.2017.01210
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Antunes DA;Rigo MM;Freitas MV;Mendes MFA;Sinigaglia M;Lizée G;Kavraki LE;Selin LK;Cornberg M;Vieira GF
• 通讯作者: Vieira GF

Weak vaccinia virus-induced NK cell regulation of CD4 T cells is associated with reduced NK cell differentiation and cytolytic activity.

• DOI: 10.1016/j.virol.2018.04.012
• 发表时间: 2018-06
• 期刊: Virology
• 影响因子: 3.7
• 作者: Hatfield SD;Daniels KA;O'Donnell CL;Waggoner SN;Welsh RM
• 通讯作者: Welsh RM

Evaluation of a method to measure HHV-6B infection in vitro based on cell size.

根据细胞大小体外测量 HHV-6B 感染的方法的评估。

• DOI: 10.1186/s12985-017-0917-z
• 发表时间: 2018
• 期刊: Virology journal
• 影响因子: 4.8
• 作者: Becerra-Artiles,Aniuska;Santoro,Tessa;Stern,LawrenceJ
• 通讯作者: Stern,LawrenceJ

Cytomegalovirus-Specific T Cell Epitope Recognition in Congenital Cytomegalovirus Mother-Infant Pairs.

• DOI: 10.3389/fimmu.2020.568217
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Materne EC;Lilleri D;Garofoli F;Lombardi G;Furione M;Zavattoni M;Gibson L
• 通讯作者: Gibson L

Virus-induced natural killer cell lysis of T cell subsets.

• DOI: 10.1016/j.virol.2019.10.003
• 发表时间: 2020-01-02
• 期刊: Virology
• 影响因子: 3.7
• 作者: Daniels KA;O'Donnell CL;Castonguay C;Strutt TM;McKinstry KK;Swain SL;Welsh RM
• 通讯作者: Welsh RM