CD4 effector contraction in influenza

流感中 CD4 效应器收缩

• 批准号: 8300101
• 负责人: SUSAN L SWAIN
• 金额: $ 40.71万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300101
• 关键词: Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Automobile Driving; B-Lymphocytes; Bacteria; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Death; Cells; Cessation of life; Complex; Contracts; Dendritic Cells; Development; Differentiation and Growth; Dose; Effector Cell; Epidemic; Epigenetic Process; Epithelial Cells; Event; Exposure to; Flu virus; Future; Generations; Health; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Infection Control; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Interleukin-2; Interleukin-6; Lead; Learning; Left; Lung; Lymphoid; MHC Class II Genes; Measures; Mediating; Mediator of activation protein; Memory; Modeling; Mus; Nature; Organ; Pathology; Peripheral; Phase; Physiologic pulse; Population; Predisposition; Process; Production; Regulation; Signal Transduction; Site; Spleen; Staging; T cell differentiation; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Transgenic Mice; Transgenic Organisms; Vaccine Design; Vaccines; Virus; autocrine; chemokine; cohort; combat; cytokine; design; flu; immunopathology; improved; in vivo; killings; lymph nodes; memory CD4 T lymphocyte; migration; pandemic disease; pathogen; programs; public health relevance; response; transcription factor; viral RNA

DESCRIPTION (provided by applicant): Protective immunity depends on memory CD4 T cells generated during initial encounter with pathogen. Naive CD4 T cells respond vigorously to influenza (Flu) virus, expanding and differentiating into a large effector population that participates in flu clearance indirectly by driving B cell antibody production and directly in the lung. Once generated, CD8 and CD4 T effector cells migrate to the lung, virus is cleared rapidly and the CD4 effector population just as quickly contracts both in the lung and elsewhere, leaving memory CD4 T cells in peripheral sites. The contraction is necessary to limit CD4 effector-mediated immunopathology in the lung, but the factors regulating contraction are as yet unknown. Flu viruses replicate in lung epithelial cells, generating billions of viruses leading to high levels of Flu antigen (Ag) presentation and as well to dramatic stimulation of the innate immune cells via recognition of viral RNA. We postulate that these innate events result in secretion of inflammatory cytokines, including TNF and IL-6, and that these factors act on the small initial population of CD4 T cells specific for Flu, to drive a complex program of response that includes both extensive expansion and differentiation to effectors as well as their commitment to die when they re-encounter Ag in the lung and periphery. We have developed a model in which we can study CD4 contraction, by transferring an easily identified "indicator" population of Flu-specific naive CD4 T cells from T cell receptor transgenic mice into a host mouse that we then infect with Flu. This allows us to visualize the contraction phase by enumerating effectors in the lung at the peak of their response and just after contraction a few days later. We will ask several key questions to evaluate our hypothesis. First we will ask if Flu Ag, expressed at the initiation of contraction, is necessary to induce the process of deletion of CD4 effectors via Ag-induced cell death. Second will ask if inflammatory cytokines, TNF and IL-6, elaborated as a result of infection, are acting to program both the effective T cell response and the contraction phase. Third we will ask if they accomplish this programming by increasing responding CD4 T cell production of IL-2 and IL-21. Identifying the factors that regulate the contraction phase should provide better understanding of the correlates of protective immunity and suggest future targets for manipulating immunopathology and memory generation. These results will help improve design of vaccines that are more effective in combating immunity but that avoid the consequences of immune-mediated pathology. PUBLIC HEALTH RELEVANCE: Infection with viruses and bacteria generate vigorous T cell immune responses that help destroy the infectious agent and also usually lead to long term immunity, so a subsequent infection will be combated swiftly and effectively. This immunity is mediated by so-called memory T cells. It is a particular importance that we learn how to best generate memory T cells. When new strains of a virus like influenza emerge, the other major kind of immunity we have, mediated by Ab, is no longer effective because the virus has changed to evade the Ab, This escape can lead to dangerous epidemics or pandemics, like the 1918 "Spanish" influenza that killed many millions, so we must depend on T cell memory. The process of memory T cell generation is not well understood. During response a very large population of T cell effectors is formed, and in the case of influenza, many of these go to the lung and attack infected cells. Once virus is gone, these "contract" leaving behind memory T cells, mostly in lymphoid organs like the spleen. In this project we will determine how this process of contraction is regulated, so that we can learn how to design vaccines that can achieve the best T cell memory.

描述（由申请人提供）：保护性免疫取决于记忆CD4 T细胞在与病原体初次相遇期间产生的记忆CD4 T细胞。幼稚的CD4 T细胞对流感（流感）病毒的剧烈反应，扩展并区分大量效应人群，通过驱动B细胞抗体的产生并直接在肺中间接参与流感清除率。一旦产生，CD8和CD4 T效应细胞迁移到肺部，就可以迅速清除病毒，并且CD4效应子种群在肺和其他地方的迅速收缩，使记忆CD4 T细胞在外围部位中留下。收缩是限制肺中CD4效应介导的免疫病理学所必需的，但是调节收缩的因素尚不清楚。流感病毒在肺上皮细胞中复制，产生数十亿个病毒，导致高水平的流感抗原（AG）表现，以及通过识别病毒RNA的急剧刺激先天免疫细胞。我们假设这些先天事件会导致包括TNF和IL-6在内的炎症细胞因子的分泌，并且这些因素对特异性流感的CD4 T细胞的初始群体的少量群体起作用，以推动复杂的反应程序，包括对效应子的广泛扩展和分化，以及它们在肺部重新遇到AG时死亡的承诺。我们已经开发了一个模型，可以通过转移来自T细胞受体转基因小鼠的流感特异性CD4 T细胞的易于识别的“指标”群体来研究CD4收缩，然后将其转移到宿主小鼠中，然后我们用流感感染。这使我们能够通过在其反应的峰值和几天后收缩之后枚举肺中的效应子来可视化收缩阶段。我们将提出几个关键问题来评估我们的假设。首先，我们将询问在收缩启动时表达的流感AG是否需要通过AG诱导的细胞死亡诱导CD4效应子的缺失过程。第二会询问因感染而阐述的炎性细胞因子TNF和IL-6是否在对有效的T细胞反应和收缩阶段进行编程。第三，我们将询问他们是否通过增加响应的IL-2和IL-21的CD4 T细胞产生来完成该编程。确定调节收缩阶段的因素应更好地理解保护性免疫的相关性，并提出处理免疫病理学和记忆产生的未来目标。这些结果将有助于改善在对抗免疫力方面更有效但避免免疫介导的病理的后果的疫苗设计。公共卫生相关性：感染病毒和细菌会产生剧烈的T细胞免疫反应，有助于破坏感染剂，并且通常会导致长期免疫力，因此随后的感染将迅速有效地打击。这种免疫力是由所谓的记忆T细胞介导的。我们学会如何最好地生成内存T细胞是一个特别重要的重要性。当像流感流感这样的病毒菌株出现时，我们通过AB介导的另一种主要的免疫力不再有效，因为该病毒已经改变以逃避AB，可能会导致危险的流行病或大流行病，例如1918年的“西班牙”流感，造成了数百万的造成T细胞存储器，因此我们必须依靠T细胞记忆。记忆T细胞产生的过程尚不清楚。在反应过程中，形成了非常大的T细胞效应子，在流感中，其中许多用于肺部并攻击受感染的细胞。病毒消失后，这些“收缩”留下了记忆T细胞，主要是在脾脏等淋巴器官中。在这个项目中，我们将确定如何调节这种收缩过程，以便我们可以学习如何设计可以实现最佳T细胞存储器的疫苗。