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:
- 金额:$ 136.21万
- 依托单位:
- 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:
- 关键词:AffinityAgonistAnabolismAntigenic DiversityAntigensBindingBiologicalBiophysicsBloodBlood donorCD1 AntigensCellsChemicalsClone CellsCommunicable DiseasesComplementComplexDataDiseaseDisease ResistanceExposure toExpression ProfilingFolic AcidFolic Acid DerivativeFrequenciesGoalsGrantHealthHigh PrevalenceHumanImmunologyImmunotherapyIndividualInfectionInvadedLeadLigand BindingLigandsLinkLipidsLiverLungMHC Class I GenesMetabolic PathwayMicrobeModelingMolecularMucous MembraneMycobacterium smegmatisMycobacterium tuberculosisNamesNatural ProductsOrganismPathogenicityPathway interactionsPatientsPeptide FragmentsPeripheral Blood Mononuclear CellPhenotypePopulationPopulation HeterogeneityPrevalenceProteinsProtocols documentationPublishingReagentRecombinantsRiboflavinSamplingScienceSignal TransductionSiteStainsStreptococcus pyogenesStructureT cell responseT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsT-cell receptor repertoireTRANCE proteinTechnologyTestingTissuesTranslatingTuberculosisVaccine TherapyWorkWorld Health Organizationadaptive immunitybasefallsimprovedinnovationinnovative technologiesinterestmetabolomemicrobialmigrationmortalitymucosal sitepathogenpathogenic microbeperipheral bloodresponsesensorsmall moleculesocial
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
粘膜相关不变T细胞(MAIT)是一种先天的类T细胞亚群,广泛存在于人类中,并得到丰富
在呼吸道里。人类MAIT细胞是由半不变的TcRα链的表达来定义的
TRAV1-2/TRAJ12/20/33及其受MHC相关的非多态MHC类分子的限制
蛋白质1(MR1)。MAIT细胞识别结核分枝杆菌,并可被源自Mtb的小有机分子激活
核黄素生物合成途径。我们已经证明,受MR1限制的T细胞可以使用不受MR1限制的TCR
TRAV1-2,并能识别不能产生核黄素的生物(化脓链霉菌)。因此,我们
将MAIT细胞定义为MR1限制性T细胞(MR1T)的子集。此外,我们发现并不是所有的MR1T都可以
基于与已知的MAIT激动剂/MR1配体5-(2-氧代亚丙基氨基)-结合的MR1四聚体-
6-D-核糖胺尿嘧啶(5-OP-RU),因为它们可以基于它们对MR1的依赖反应来定义
微生物感染和与交替的MR1四聚体结合。我们已经为以下方面生成了管道方法
鉴定新的微生物来源的MR1抗原,并证明肺中的MR1T具有特征
通过寡克隆浓缩,可能是由这些抗原驱动的。总而言之,这些数据支持具体目标
将1)定义由M.smeg/Mtb的MR1提出的配体的谱系,以及
通过MR1定义其演示的结构基础。我们重点研究结核分枝杆菌与其疾病的相关性
人类健康,也来自我们的初步数据显示MR1反应性T细胞迁移到肺
在结核分枝杆菌感染期间。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,并定义了他们识别MR1-的结构基础
抗原复合体。这是来自我们和其他人的初步数据的明显延伸,表明
MR1T种群包含以前未被赏识的多样性。我们试图知道这种多样性是否在
TCR谱系推动了抗原的选择性。与目标1和目标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。我们
假设具有不同TCR谱系的MR1T细胞选择性地在感染的组织部位扩张
通过MR1对微生物/配体识别的反应。在这里,我们的重点将是MTB,我们将利用
Waltz博士(开普敦)提取肺(BAL)和PBMC样本的专业知识和患者可获得性
感染和控制个体。最终,该项目的工作将支持针对MR1T细胞的
疫苗和免疫疗法作为提高接触结核分枝杆菌后疾病抵抗力的一种手段。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Erin June Adams其他文献
Erin June Adams的其他文献
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{{ truncateString('Erin June Adams', 18)}}的其他基金
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多发性骨髓瘤细胞系中非经典 MHC 相关蛋白 MR1 内源配体库的研究
- 批准号:
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Molecular and functional investigation of the role of HLA-F in immune regulation
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通过分子和功能方法确定非经典 I 类分子的起源
- 批准号:
10501472 - 财政年份:2022
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