T regulatory cells and immunity in tuberculosis

描述（由申请人提供）：表达Foxp 3的调节性T细胞（T细胞）是预防自身免疫所必需的CD 4 + T细胞亚群，也可以抑制抗微生物免疫应答，但其在结核病期间的活性在很大程度上尚未探索。我们的初步数据表明，在结核病期间，T细胞在感染部位扩展和积累，并有能力抑制提供保护的免疫机制。重要的是，我们还表明，这两种特性，扩增和抑制，优先表现为结核分枝杆菌（Mtb）抗原特异性的T细胞。我们建议研究结核病期间T细胞在限制保护性免疫反应中的影响。在目标1中，我们将描述结核病期间应答的T细胞的起源。我们将确定它们是否来源于预先存在的T细胞群和/或CD 4+效应T细胞是否被诱导表达Foxp 3并成为结核病背景下的调节细胞。在目标2中，我们将讨论结核病中T淋巴细胞的特异性。将确定免疫应答早期阶段Mtb特异性T reg抑制的长期后果。将鉴定结核病期间T细胞识别的MHC II类限制性分枝杆菌抗原，并确定它们与效应T细胞识别的Mtb抗原是否相同或不同。在目的3中，我们将确定增加Mtb特异性T细胞的前体频率对Mtb特异性效应T细胞的功能活性的影响。将评估T细胞对效应T细胞引发、运输和细胞因子产生的影响。该提议利用小鼠模型中的各种免疫学工具来实现其目标。该建议所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，以规避T reg介导的保护性免疫应答抑制。公共卫生相关性：限制免疫系统根除结核分枝杆菌（结核病的病原体）能力的因素知之甚少。在这里，我们测试的想法，病原体特异性T淋巴细胞的子集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。

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.