T regulatory cells and immunity in tuberculosis

结核病中的 T 调节细胞和免疫

• 批准号: 8091459
• 负责人: KEVIN B URDAHL
• 金额: $ 48.15万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091459
• 关键词: Address; Antigens; Autoimmunity; Bacteria; CD4 Positive T Lymphocytes; Cells; Data; Frequencies; Goals; Granuloma; Health; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Infection; Infection Control; Lung; MHC Class II Genes; Mediating; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Population; Production; Proliferating; Property; Regulatory T-Lymphocyte; Relative (related person); Research; Role; Site; Specificity; Staging; T cell response; T-Lymphocyte; Testing; Tuberculosis; Vaccine Design; Vaccines; Work; antimicrobial; cytokine; improved; in vivo; lymph nodes; mouse model; mycobacterial; pathogen; prevent; tool; trafficking; tuberculosis immunity; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): Foxp3-expressing regulatory T cells (T regs), a subset of CD4+ T cells that are essential for preventing autoimmunity, can also suppress anti-microbial immune responses, but their activity during tuberculosis is largely unexplored. Our preliminary data show that T regs expand and accumulate at sites of infection during tuberculosis and have the capacity to suppress immune mechanisms that provide protection. Importantly, we have also shown that both of these properties, expansion and suppression, are manifested preferentially by T regs that are specific for Mycobacterium tuberculosis (Mtb) antigens. We propose to investigate the influence of T regs in limiting protective immune responses during tuberculosis. In Aim 1 we will characterize the origin of T regs that respond during tuberculosis. We will determine whether they are derived from populations of pre-existing T regs and/or whether CD4+ effector T cells are induced to express Foxp3 and become regulatory cells in the setting of tuberculosis. In Aim 2 we will address the specificity of T regs in tuberculosis. The long-term consequences of Mtb-specific T reg suppression during the early stages of the immune response will be determined. MHC class II-restricted mycobacterial antigens recognized by T regs during tuberculosis will be identified, and we will determine whether they are the same, or different, as Mtb antigens recognized by effector T cells. In Aim 3 we will determine the effect of increasing the precursor frequency of Mtb-specific T regs on the functional activity of Mtb-specific effector T cells. The influence of T regs on effector T cell priming, trafficking, and cytokine production will be assessed. This proposal takes advantage of a wide variety of immunologic tools in the mouse model to accomplish its goals. Understanding generated by this proposal will be highly relevant to vaccine design and testing, and may suggest improved immunization strategies that circumvent T reg-mediated suppression of protective immune responses. PUBLIC HEALTH RELEVANCE: The factors that limit the immune system's ability to eradicate Mycobacterium tuberculosis, the causative agent of tuberculosis, are poorly understood. Here we test the idea that a subset of pathogen-specific T lymphocytes impairs the ability of the immune system to clear the bacteria. Understanding the role of these cells in suppressing immunity during tuberculosis has the potential to inform new and effective vaccine strategies that circumvent their activity and enhance pathogen clearance.

描述（由申请人提供）：表达foxp3的调节性T细胞（T regs）是CD4+ T细胞的一个亚群，对预防自身免疫至关重要，也可以抑制抗微生物免疫反应，但其在结核病中的活性在很大程度上未被探索。我们的初步数据表明，T regs在结核病感染部位扩张和积累，并具有抑制提供保护的免疫机制的能力。重要的是，我们还发现这两种特性，即扩增和抑制，都是由结核分枝杆菌（Mtb）抗原特异性的T regs优先表现出来的。我们建议研究T regs在结核病期间限制保护性免疫反应中的影响。在目标1中，我们将描述结核期间应答的T regs的起源。我们将确定它们是否来源于预先存在的T regs群体和/或CD4+效应T细胞是否被诱导表达Foxp3并成为结核病背景下的调节细胞。在目标2中，我们将讨论结核中T regs的特异性。在免疫应答的早期阶段，mmb特异性T reg抑制的长期后果将被确定。将鉴定结核期间被T细胞识别的MHC ii类限制性分枝杆菌抗原，我们将确定它们是否与效应T细胞识别的Mtb抗原相同或不同。在Aim 3中，我们将确定增加mmb特异性T regs前体频率对mmb特异性效应T细胞功能活性的影响。将评估T regs对效应T细胞启动、运输和细胞因子产生的影响。该建议利用小鼠模型中的多种免疫工具来实现其目标。这一建议产生的理解将与疫苗设计和测试高度相关，并可能建议改进免疫策略，以绕过T reg介导的保护性免疫反应抑制。公共卫生相关性：限制免疫系统根除结核分枝杆菌（结核的病原体）能力的因素尚不清楚。在这里，我们测试了病原体特异性T淋巴细胞亚群损害免疫系统清除细菌的能力的想法。了解这些细胞在结核病期间抑制免疫中的作用，有可能为新的有效疫苗策略提供信息，以绕过它们的活动并增强病原体清除。