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（由申请方提供）：保护性免疫力取决于初次接触病原体期间产生的记忆性CD 4 T细胞。初始CD 4 T细胞对流感（Flu）病毒反应强烈，扩增并分化成大的效应细胞群，其通过驱动B细胞抗体产生间接参与流感清除，并直接在肺中参与流感清除。一旦产生，CD 8和CD 4 T效应细胞迁移到肺，病毒被迅速清除，CD 4效应细胞群在肺和其他地方同样迅速收缩，在外周部位留下记忆性CD 4 T细胞。这种收缩对于限制肺中CD 4效应介导的免疫病理学是必要的，但调节收缩的因素尚不清楚。流感病毒在肺上皮细胞中复制，产生数十亿病毒，导致高水平的流感抗原（Ag）呈递，以及通过识别病毒RNA显著刺激先天免疫细胞。我们假设这些先天事件导致炎性细胞因子的分泌，包括TNF和IL-6，并且这些因子作用于对流感特异性的小的初始CD 4 T细胞群体，以驱动复杂的应答程序，包括广泛的扩增和分化为效应物以及当它们在肺和外周中再次遇到Ag时它们死亡的承诺。我们已经开发了一种模型，其中我们可以研究CD 4收缩，通过转移一个容易识别的“指示”群体的流感特异性幼稚CD 4 T细胞从T细胞受体转基因小鼠到宿主小鼠，我们然后感染流感。这使我们能够通过计数肺中的效应器在其响应的峰值和几天后的收缩后来可视化收缩阶段。我们将提出几个关键问题来评估我们的假设。首先，我们将询问在收缩开始时表达的Flu Ag是否是通过Ag诱导的细胞死亡诱导CD 4效应子缺失过程所必需的。第二个问题是炎症细胞因子，TNF和IL-6，作为感染的结果，是否对有效的T细胞反应和收缩期起作用。第三，我们将询问它们是否通过增加响应性CD 4 T细胞产生IL-2和IL-21来完成这种编程。确定调节收缩期的因素应该提供更好的理解保护性免疫的相关性，并建议未来的目标，操纵免疫病理学和记忆的产生。这些结果将有助于改进疫苗的设计，这些疫苗在对抗免疫方面更有效，但避免了免疫介导的病理后果。公共卫生关系：病毒和细菌感染会产生强烈的T细胞免疫反应，有助于破坏感染因子，通常也会导致长期免疫，因此随后的感染将得到迅速有效的打击。这种免疫力是由所谓的记忆T细胞介导的。我们学习如何最好地产生记忆T细胞是特别重要的。当新的流感病毒株出现时，我们拥有的另一种主要的免疫力，由抗体介导，不再有效，因为病毒已经改变以逃避抗体，这种逃避可能导致危险的流行病或大流行病，就像1918年杀死数百万人的“西班牙”流感一样，所以我们必须依赖T细胞记忆。记忆T细胞的产生过程还不清楚。在反应过程中，形成了非常大的T细胞效应器群体，在流感的情况下，其中许多进入肺部并攻击感染的细胞。一旦病毒消失，这些“合同”留下记忆T细胞，主要是在淋巴器官如脾脏。在这个项目中，我们将确定这种收缩过程是如何调节的，这样我们就可以学习如何设计能够实现最佳T细胞记忆的疫苗。