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

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

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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.

项目摘要/摘要粘膜相关的不变T（MAIT）细胞是人类普遍存在的先天性T细胞子集，并富集在气道。人类Mait细胞已通过半不变TCRα链的表达来定义 TRAV1-2/TRAJ12/20/33及其受非甲基型MHC类I类分子的限制，与MHC相关蛋白质1（MR1）。 Mait细胞识别MTB，可以被小的有机分子激活，这些分子源自核黄素生物合成途径。我们已经表明，MR1限制的T细胞可以使用不使用的TCR TRAV1-2，并且可以识别无法产生核黄素的生物（s。为）。因此，我们将MAIT细胞定义为MR1限制的T细胞的子集（MR1TS）。此外，我们发现并非所有MR1T都可以根据MR1四聚体与已知的Mait激动剂 / MR1配体5-（2-氧化丙基乙酰氨基）结合定义 - 6-d-ribitylaminouracil（5-op-ru），可以根据其MR1依赖性响应来定义它们微生物感染并与替代MR1四聚体结合。我们已经生成了一个管道方法鉴定新的，微生物衍生的MR1抗原，并证明肺中的MR1T是表征的通过寡克隆富集，可能由这些抗原驱动。这些数据共同支持特定目的这笔赠款是1）定义M.Smeg/MTB和MR1提出的配体的曲目定义MR1演示的结构基础。我们专注于MTB的疾病与人类健康，也来自我们的初步数据，证明MR1反应性T细胞迁移到肺在MTB感染期间。我们的目标2是定义识别抗原的MR1T的T细胞库由M.Smeg/MTB的MR1提出，并定义了它们对MR1-的认可的结构基础抗原复合物。这是从我们和其他人的初步数据中明显的扩展，证明了这一点 MR1T人群包含以前未欣赏的多样性。我们试图知道这种多样性是否 TCR曲目驱动抗原选择性。与目标1和2直接相关的是我们的目标3，它将决定人类健康和疾病中MR1-配体/MR1T细胞选择性的生物学。我们假设具有潜水员TCR库的MR1T细胞选择性地在感染的组织部位扩展通过MR1对微生物/配体识别的响应。在这里，我们的重点将放在MTB上，我们利用 Waltz博士（Capetown）的专业知识和患者可访问性从肺（BAL）和PBMC样本中得出感染并控制个体。最终，该项目的工作将支持针对的MR1T单元格接触MTB后，疫苗和免疫疗法是提高对疾病抗性的一种手段。