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

基本信息

批准号：
10164711
负责人：
DAVID M. LEWINSOHN
金额：
$ 68.33万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10164711
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

项目摘要

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.

项目概要对于人类来说，气溶胶暴露于结核分枝杆菌 (Mtb) 的结果是不同的，范围从无感染和/或清除到进行性疾病。粘膜的一个关键作用是确定接触 Mtb 后的结果，但人们对此仍知之甚少。相关不变 T (MAIT) 细胞是人类中普遍存在的先天性 T 细胞亚群，富含人类 MAIT 细胞通过半不变 TCRα 链 TRAV1- 的表达来定义。 2/TRAJ12/20/33 及其受非多态性 MHC I 类分子、MHC 相关蛋白 1 的限制 (MR1)。MAIT 细胞识别 Mtb，并且可以被核黄素衍生的小有机分子激活。我们已经证明 MR1 限制性 T 细胞可以使用非 TRAV1-2 的 TCR，并且可以识别不能产生核黄素的生物体{Meermeier，2016年测试，我们定义MAIT。细胞作为 MR1 限制性 T 细胞 (MR1T) 的子集此外，我们发现并非所有 MR1T 都可以定义。基于与已知 MAIT 激动剂/MR1 配体 5-(2-氧亚丙基氨基)-6-D- 结合的 MR1 四聚体 ribitylaminouracil (5-OP-RU)，因为它们可以根据对微生物的 MR1 依赖性反应来定义我们为新型分枝杆菌衍生的 MR1 提供了证据。抗原，并证明肺中的 MR1T 具有寡克隆富集的特征，可能最后，我们发现肺内的 MR1T 具有抗微生物效应能力。这些发现提出了一种有趣的可能性，即肺部驻留的 Mtb 反应性 MR1T 可能发挥专门的作用具体来说，这可能是释放的结果。促炎细胞因子如 IFN-γ 的作用，以及它们的直接抗微生物活性。我们将使用胸部成像（PET/CT 或传统放射线照相）来确定 HIV 感染者和患者的健康状况接触 Mtb 后未感染的个体将根据症状来定义患有临床结核病的个体。 CXR、PET/CT 阴性的无症状个体中存在疾病、异常 CXR 和培养阳性。将用于对耐药者（PET/CT 阴性）与亚临床疾病者进行分类（PET/CT 阳性）我们勇敢地面对肺部驻留 MR1T 的识别和控制能力。结核分枝杆菌感染将带来良好的临床结果。在此应用中，我们将解决以下问题：1）流行率和效应器是什么接触 Mtb 和感染 HIV 后，肺部和外周血中 MR1T 细胞的功能？ MR1T TCR 使用和配体歧视与 Mtb 暴露后的结果有何关系？ 3) MR1T 细胞如何控制 Mtb 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提高接触结核分枝杆菌后的抗病能力的一种手段。