T regulatory cells and immunity in tuberculosis

结核病中的 T 调节细胞和免疫

• 批准号: 7654539
• 负责人: KEVIN B URDAHL
• 金额: $ 37.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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/7654539
• 关键词: Address; Antigens; Autoimmunity; Bacteria; CD4 Positive T Lymphocytes; Cells; Data; Frequencies; Goals; Granuloma; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Infection; Infection Control; Lung; MHC Class II Genes; Mediating; Mus; Mycobacterium tuberculosis; Population; Production; Proliferating; Property; Relative (related person); Research; Role; Site; Specificity; Staging; T-Lymphocyte; Testing; Tuberculosis; Vaccine Design; Vaccines; Work; antimicrobial; cytokine; improved; in vivo; lymph nodes; mouse model; mycobacterial; pathogen; prevent; public health relevance; response; tool; trafficking; tuberculosis immunity; vaccine efficacy

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 细胞的一个子集，对于预防自身免疫至关重要，也可以抑制抗微生物免疫反应，但它们在结核病期间的活性很大程度上尚未被探索。我们的初步数据表明，T reg 在结核病期间在感染部位扩增和积累，并具有抑制提供保护的免疫机制的能力。重要的是，我们还表明，扩张和抑制这两种特性均优先由结核分枝杆菌 (Mtb) 抗原特异性的 T reg 表现出来。我们建议研究 T regs 在限制结核病期间保护性免疫反应中的影响。在目标 1 中，我们将描述在结核病期间做出反应的 T reg 的起源。我们将确定它们是否源自预先存在的 T reg 群体和/或 CD4+ 效应 T 细胞是否被诱导表达 Foxp3 并在结核病中成为调节细胞。在目标 2 中，我们将解决结核病中 T reg 的特异性。在免疫反应的早期阶段，结核分枝杆菌特异性 T reg 抑制的长期后果将被确定。我们将鉴定结核病期间 T reg 识别的 MHC II 类限制性分枝杆菌抗原，并且我们将确定它们与效应 T 细胞识别的 Mtb 抗原是否相同或不同。在目标 3 中，我们将确定增加 Mtb 特异性 T reg 的前体频率对 Mtb 特异性效应 T 细胞功能活性的影响。将评估 T reg 对效应 T 细胞启动、运输和细胞因子产生的影响。该提案利用小鼠模型中的多种免疫学工具来实现其目标。该提案产生的理解将与疫苗设计和测试高度相关，并可能提出改进的免疫策略，以规避 T reg 介导的保护性免疫反应抑制。公共卫生相关性：人们对限制免疫系统根除结核病病原体——结核分枝杆菌的能力的因素知之甚少。在这里，我们测试了这样一种观点，即病原体特异性 T 淋巴细胞的子集会损害免疫系统清除细菌的能力。了解这些细胞在结核病期间抑制免疫力的作用有可能为规避其活性并增强病原体清除的新的有效疫苗策略提供信息。