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.
项目总结/文摘
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
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Molecular and functional investigation of the role of HLA-F in immune regulation
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$ 136.21万 - 项目类别:
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