T cell recognition of the MR1 presented microbial metabolome

T 细胞识别 MR1 呈递的微生物代谢组

基本信息

批准号：
9975096
负责人：
Erin June Adams
金额：
$ 136.21万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975096
关键词：
Affinity Agonist Anabolism Antigenic Diversity Antigens Binding Biological Biophysics Blood Blood donor CD1 Antigens Cells Chemicals Clone Cells Communicable Diseases Complement Complex Data Disease Disease Resistance Exposure to Expression Profiling Folic Acid Folic Acid Derivative Frequencies Goals Grant Health High Prevalence Human Immunology Immunotherapy Individual Infection Invaded Lead Ligand Binding Ligands Link Lipids Liver Lung MHC Class I Genes Metabolic Pathway Microbe Modeling Molecular Mucous Membrane Mycobacterium smegmatis Mycobacterium tuberculosis Names Natural Products Organism Pathogenicity Pathway interactions Patients Peptide Fragments Peripheral Blood Mononuclear Cell Phenotype Population Population Heterogeneity Prevalence Proteins Protocols documentation Publishing Reagent Recombinants Riboflavin Sampling Science Signal Transduction Site Stains Streptococcus pyogenes Structure T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TRANCE protein Technology Testing Tissues Translating Tuberculosis Vaccine Therapy Work World Health Organization adaptive immunity base falls improved innovation innovative technologies interest metabolome microbial migration mortality mucosal site pathogen pathogenic microbe peripheral blood response sensor small molecule social

项目摘要

Project Summary/Abstract 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 (S. pyogenes) that cannot produce riboflavin. 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 have generated a pipeline approach for identifying new, microbially-derived MR1 antigens, and demonstrate that MR1Ts in the lung are characterized by oligoclonal enrichments, possibly driven by these antigens. Together, these data support the specific aims of this grant which are to 1) define the repertoire of ligands presented by MR1 from M. smeg/Mtb and define the structural basis of their presentation by MR1. We focus on Mtb for its disease relevance to human health but also from our preliminary data demonstrating migration of MR1 reactive T cells to the lung during Mtb infection. Our Aim 2 is to define the T cell repertoire of MR1Ts recognizing antigens presented by MR1 from M. smeg/Mtb and define the structural basis of their recognition of the MR1- antigen complex. This is an obvious extension from preliminary data from us and others demonstrating that the MR1T population contains diversity previously unappreciated. We seek to know whether this diversity in the TCR repertoire drives antigen selectivity. Directly related to Aims 1 & 2 is our Aim 3 which will determine the biological significance of MR1-ligand/MR1T cell selectivity in human health and disease. We hypothesize that MR1T cells with a diverse TCR repertoire selectively expand at infected tissue sites in response to microbe/ligand recognition via MR1. Here our focus will be on Mtb, and we capitalize on the expertise and patient accessibility of Dr. Waltz (Capetown) to derive lung (BAL) and PBMC samples from infected and control individuals. 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/摘要粘膜相关不变 T (MAIT) 细胞是人类中普遍存在的先天性 T 细胞亚群，并且丰富人类 MAIT 细胞是通过半不变 TCRα 链的表达来定义的。 TRAV1-2/TRAJ12/20/33 及其受非多态性 MHC I 类分子（MHC 相关）的限制蛋白 1 (MR1)。MAIT 细胞可识别 Mtb，并可被源自 Mtb 的有机小分子激活。我们已经证明，MR1 限制性 T 细胞可以使用非 MR1 限制性 TCR。 TRAV1-2，并且可以识别不能产生核黄素的生物体（化脓性链球菌），我们进行了测试。将 MAIT 细胞定义为 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。基于与已知 MAIT 激动剂/MR1配体 5-(2-氧亚丙基氨基)-结合的 MR1 四聚体来定义 6-D-核糖基氨基尿嘧啶 (5-OP-RU)，因为它们可以根据 MR1 依赖性反应来定义我们已经开发了一种用于微生物感染和与替代 MR1 四聚体结合的管道方法。鉴定新的微生物衍生的 MR1 抗原，并证明肺部 MR1T 的特征通过寡克隆富集，可能由这些抗原驱动，这些数据共同支持了特定目标。该资助的目的是 1) 定义来自 M. smeg/Mtb 的 MR1 呈现的配体库和我们通过 MR1 定义其表达的结构基础。我们关注 Mtb，因为它与疾病相关。人类健康，而且我们的初步数据显示 MR1 反应性 T 细胞迁移到肺部我们的目标 2 是确定 MR1T 识别抗原的 T 细胞库。由来自 M. smeg/Mtb 的 MR1 提出，并定义了他们识别 MR1-的结构基础这是我们和其他人的初步数据的明显延伸，证明了这一点。 MR1T 群体包含以前未被认识到的多样性。 TCR 库驱动抗原选择性，与目标 1 和 2 直接相关的是我们的目标 3，它将决定。 MR1-配体/MR1T细胞选择性在人类健康和疾病中的生物学意义。具有多种 TCR 库的 MR1T 细胞选择性地在感染组织部位扩增通过 MR1 对微生物/配体识别做出反应这里我们的重点是 Mtb，我们利用 Waltz 博士（开普敦）的专业知识和患者可及性，可从其中获取肺 (BAL) 和 PBMC 样本最终，该项目的工作将支持 MR1T 细胞靶向。疫苗和免疫疗法是提高接触结核分枝杆菌后的疾病抵抗力的一种手段。