T regulatory cells and immunity in tuberculosis

描述(申请人提供)：Foxp3表达的调节性T细胞(Tregs)是防止自身免疫所必需的CD4+T细胞的一个亚群，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在很大程度上还没有被探索。我们的初步数据显示，在结核病期间，T调节器在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，我们还证明了这两种属性，即扩张和抑制，都优先表现为针对结核分枝杆菌(Mtb)抗原的T调节器。我们建议研究T调节子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有反应的T调节细胞的起源。我们将确定它们是否是来自预先存在的T调节细胞群体和/或是否诱导CD4+效应T细胞表达Foxp3并成为结核病背景下的调节细胞。在目标2中，我们将解决T调节蛋白在结核病中的特异性。在免疫反应的早期阶段，结核分枝杆菌特异性T受体抑制的长期后果将被确定。我们将确定在结核病过程中T regs识别的MHC II类限制性分枝杆菌抗原，并确定它们与效应器T细胞识别的Mtb抗原相同还是不同。在目标3中，我们将确定增加结核分枝杆菌特异性T细胞前体频率对结核分枝杆菌特异性效应T细胞功能活性的影响。将评估T调节因子对效应器T细胞启动、运输和细胞因子产生的影响。这一建议利用了小鼠模型中的各种免疫学工具来实现其目标。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。与公共卫生相关：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，目前还知之甚少。在这里，我们测试了这样的想法，即病原体特异性T淋巴细胞的子集损害了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的作用，可能会为绕过它们的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.