Identification of human Mtb-specific T cell signatures that are associated

确定结核分枝杆菌（Mtb）感染的控制和保护的免疫相关性是 对于设计结核病疫苗至关重要。我们TBRU应用程序的总体目标是确定 与Mtb感染的不同结果相关的抗原特异性T细胞应答：清除， 持续性和进展为活动性疾病。我们目前缺乏知识或工具来区分 携带持续性Mtb感染的个体与可能通过以下途径解决感染的个体 免疫介导的细菌清除。在项目1中，我们将重点关注“人类结核特异性T细胞的鉴定”。 与已解决的和持续的Mtb感染相关的细胞特征”。我们将检验这个假设 不同的Mtb特异性记忆T细胞谱与细菌清除或持久性相关。这 我们的数据表明，不同的抗原特异性记忆T细胞表型和功能， 与LTBI、活动性TB疾病和临床消退的TB相关。我们建议使用 化疗介导的Mtb清除模型，作为治疗方案 LTBI应导致细菌的显著减少或消除。我们将招募LTBI患者， 低暴露环境（Atlanta，GA），并系统地比较它们的抗原特异性T细胞应答 治疗前后我们将描绘结核分枝杆菌特异性记忆识别的抗原谱 CD 4和CD 8 T细胞，表征其记忆表型、功能能力和转录能力。 配置文件（目标1）。使用统计分析，我们将推导出代表以下特征的结核分枝杆菌特异性T细胞特征： 在非人灵长类动物（NHP）中进行细菌清除和持久性研究，并对其进行评价（与项目3一起）， 确定这些特征在肯尼亚初次治疗的LTBI患者中的患病率（目标2）。我们 将纵向评估Mtb特异性记忆T细胞应答的动态及其稳态 在LTBI（目标3）的营业额。我们还将比较清除/持久性特征与 结核病进展（与项目2）。总的来说，这些研究将为结核病的保护性免疫提供见解 和新的工具，以评估结核杆菌的持久性或清除LTBI。

Identifying immune correlates of control and protection to Mycobacterium tuberculosis (Mtb) infection is essential for designing vaccines for TB. The overall goals of our TBRU application are to identify antigen-specific T cell responses that are associated with distinct outcomes of Mtb infection: clearance, persistence, and progression to active disease. We currently lack the knowledge or tools to distinguish individuals who harbor persistent Mtb infection from those who may have resolved infection via immune-mediated clearance of bacteria. In Project 1 we will focus on "Identification of human Mtb-specific T cell signatures that are associated with resolved and persistent Mtb infection". We will test the hypothesis that distinct Mtb-specific memory T cell profiles are associated with bacterial clearance or persistence. This is supported by our data showing that distinct antigen-specific memory T cell phenotypes and functions are associated with LTBI, active TB disease and clinically resolved TB. We propose to use chemotherapy-mediated clearance to model immune-mediated clearance of Mtb, as the treatment regimen for LTBI should result in significant reduction or elimination of bacteria. We will enroll individuals with LTBI in a low-exposure setting (Atlanta, GA) and systematically compare their antigen-specific T cell responses before and after treatment. We will delineate the spectrum of antigens recognized by Mtb-specific memory CD4 and CD8 T cells, characterize their memory phenotypes, functional capacities and transcriptional profiles (Aim 1). Using statistical analyses, we will derive Mtb-specific T cell signatures that represent bacterial clearance and persistence and evaluate these (with Project 3), in non-human primates (NHP) and determine the prevalence of these signatures in treatment-naive individuals with LTBI in Kenya (Aim 2). We will longitudinally assess the dynamics of Mtb-specific memory T cell responses and their homeostatic turnover in LTBI (Aim3). We will also compare clearance/persistence signatures with those associated with progression to TB (with Project 2). Overall, these studies will provide insights into protective immunity to TB and new tools to evaluate Mtb persistence or clearance in LTBI.