Lung Resident, MR1-Restricted T Cells: Association with Differential Outcomes Following Exposure to M. Tuberculosis

肺驻留、MR1 限制性 T 细胞：与接触结核分枝杆菌后不同结果的关联

• 批准号: 9593711
• 负责人: DAVID M. LEWINSOHN
• 金额: $ 68.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9593711
• 关键词: Address; Aerosols; Agonist; Anabolism; Antigens; Bacteria; Binding; Blood; Cells; Chest; Clinical; Clone Cells; Diagnostic radiologic examination; Dipeptidyl-Peptidase IV; Discrimination; Disease; Disease Resistance; Early Diagnosis; Effector Cell; Exposure to; Favorable Clinical Outcome; Flow Cytometry; HIV; HIV Infections; Health Status; Human; Image; Immune; Immune system; Immunotherapy; Individual; Infection; Infection Control; Inflammatory; Interferon Type II; Ligands; Lung; MHC Class I Genes; Microbe; Mucous Membrane; Mycobacterium tuberculosis; Organism; Outcome; PET/CT scan; Pathway interactions; Phenotype; Play; Prevalence; Progressive Disease; Proteins; Resistance; Riboflavin; Role; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Thoracic Radiography; Tuberculosis; Vaccine Therapy; Work; antimicrobial; base; cohort; cytokine; fungus; improved; microbial; mycobacterial; novel; peripheral blood; response; single cell sequencing; transcriptome sequencing

Project Summary In humans, aerosol exposure to Mycobacterium tuberculosis (Mtb) results is disparate outcomes, ranging from no-infection and/or clearance, to progressive disease. Lung-resident, immune effectors likely play a critical role is determining the outcome following exposure to Mtb, yet remain poorly understood. Mucosal associated invariant T (MAIT) cells are an innate-like T cell subset prevalent in humans and enriched in the airway. Human MAIT cells have been defined by the expression of the semi-invariant TCRα chain TRAV1- 2/TRAJ12/20/33 and their restriction by the non-polymorphic MHC class I-like molecule, MHC-related protein 1 (MR1). MAIT cells recognize Mtb and can be activated by small organic molecules, derived from the riboflavin biosynthesis pathway. We have shown that MR1-restricted T cells can use TCRs that are not TRAV1-2, and can recognize organisms that cannot produce riboflavin {Meermeier, 2016}. Consequently, we define MAIT cells as a subset of MR1-restricted T cells (MR1Ts). Furthermore, we find that not all MR1Ts can be defined based on MR1 tetramer bound to the known MAIT agonist / MR1 ligand 5-(2-oxopropylideneamino)-6-D- ribitylaminouracil (5-OP-RU), in that they can be defined based on their MR1-dependent response to microbial infection and binding to alternate MR1 tetramers. We provide evidence for novel, mycobacterially-derived MR1 antigens, and demonstrate that MR1Ts in the lung are characterized by oligoclonal enrichments, possibly driven by these antigens. Finally, we find that lung-resident MR1Ts have anti-microbial effector capacity. These findings raise the intriguing possibility that lung resident, Mtb-reactive, MR1Ts could play a specialized role in the early detection and control of infection due to Mtb. Specifically, this could be the result of the release of pro-inflammatory cytokines such as IFN-γ, as well as by their direct anti-microbial activity. In this application, we will use thoracic imaging (PET/CT or traditional radiography) to define the health status of HIV infected and uninfected individuals following exposure to Mtb. Those with clinical TB will be defined by symptomatic disease, abnormal CXR, and culture positivity. Among asymptomatic individuals with a negative CXR, PET/CT will be used to categorize those who are resistant (PET/CT negative) vs those with subclinical disease (PET/CT positive). We hypothesize that lung resident MR1Ts with the capacity to recognize and control infection with Mtb will be associated with favorable clinical outcomes. In this application, we will address the following questions: 1) What is the prevalence and effector function of MR1T cells in the lung and peripheral blood following exposure to Mtb and in the setting of HIV? 2) What is the relationship of MR1T TCR usage and ligand discrimination to outcomes following exposure to Mtb? 3) How might MR1T cells control infection with Mtb? Ultimately, the work from this project would support MR1T cell targeted vaccines and immune-therapies as a means to improve resistance to disease following exposure to Mtb.

项目摘要 在人类中，气雾剂暴露于结核分枝杆菌(Mtb)结果是不同的结果， 范围从无感染和/或清除，到进展性疾病。肺居留，免疫效应器可能发挥作用 一个关键的作用是决定接触结核分枝杆菌后的结果，但仍然知之甚少。粘膜 相关不变T细胞(MAIT)是一种先天的类T细胞亚群，普遍存在于人类中，并富含在 气道口。人类MAIT细胞是由半不变的TCRTRAV1-α链的表达来定义的 2/TRAJ12/20/33及其受非多态MHC类分子MHC相关蛋白1的限制 (MR1)。MAIT细胞识别结核分枝杆菌，并可被核黄素衍生的小有机分子激活 生物合成途径。我们已经证明，受MR1限制的T细胞可以使用不是TRAV1-2的TCR，并且 能够识别不能产生核黄素的生物(Meermeier，2016)。因此，我们将MAIT定义为 细胞作为MR1限制性T细胞(MR1T)的一个亚群。此外，我们发现并不是所有的MR1T都可以定义 基于已知的MAIT激动剂/MR1配体结合的MR1四聚体5-(2-氧代亚丙叉氨基)-6-D- Ribitylamineouracil(5-OP-RU)，因为它们可以根据它们对微生物的MR1依赖反应来定义 感染并与交替的MR1四聚体结合。我们为新的分支杆菌衍生的MR1提供了证据 抗原，并证明肺中的MR1T具有寡克隆性富集性，可能 在这些抗原的驱动下。最后，我们发现驻肺的MR1T具有抗微生物效应器的能力。 这些发现提出了一种耐人寻味的可能性，即肺部居民，结核分枝杆菌反应性，MR1TS可能扮演一种特殊的 在早期发现和控制结核分枝杆菌感染方面的作用。具体地说，这可能是发布的结果 如干扰素-γ等促炎细胞因子以及它们的直接抗微生物活性。在此应用程序中， 我们将使用胸部成像(PET/CT或传统放射学)来确定艾滋病毒感染者的健康状况和 接触结核分枝杆菌后未受感染的个人。临床上患有结核病的人将根据症状来定义 疾病、CXR异常和培养阳性。在CXR阴性的无症状个体中，PET/CT 将用于将耐药者(PET/CT阴性)与亚临床疾病者进行分类 (PET/CT阳性)。我们假设肺部居民的核磁共振成像具有识别和控制能力 感染结核分枝杆菌将与良好的临床结果相关。 在本应用程序中，我们将解决以下问题：1)什么是流行率和效应者 结核分枝杆菌感染和HIV感染后肺和外周血中MR1T细胞的功能 MR1T、TCR的使用和配基歧视与接触结核杆菌后的结果有什么关系？ 3)MR1T细胞如何控制结核分枝杆菌感染？ 最终，该项目的工作将支持MR1T细胞靶向疫苗和免疫疗法 作为一种提高对结核分枝杆菌暴露后疾病抵抗力的手段。