TCR signal strength and iNKT cell subset development
TCR 信号强度和 iNKT 细胞亚群发育
基本信息
- 批准号:9981614
- 负责人:
- 金额:$ 38.16万
- 依托单位:
- 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:2018-08-10 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAntigenic SpecificityAntigensAutoimmune DiseasesAutoimmunityAvidityBiologicalCD1d antigenCell CountCell membraneCell physiologyCellsCommunicable DiseasesComplexCuesCytoskeletonCytotoxic T-LymphocytesDataDefectDevelopmentDisease ResistanceEventExhibitsGene ExpressionGeneticGoalsHealthHomeostasisHumanImmuneImmune responseImmunityImmunologicsInfectionInjuryKnowledgeLigandsLipidsMHC Class I GenesMajor Histocompatibility ComplexMalignant NeoplasmsMetabolic DiseasesMetabolismMissionMouse StrainsMusMutationNaturePerceptionPlayPopulationPredispositionPregnancyProcessProtein Tyrosine KinaseReceptor ActivationReceptor SignalingRegulationResearchRoleSensitivity and SpecificitySignal TransductionSignal Transduction PathwaySpecific qualifier valueT cell differentiationT cell therapyT-Cell Antigen Receptor SpecificityT-Cell DevelopmentT-Cell ReceptorT-LymphocyteT-Lymphocyte Gene RearrangementT-Lymphocyte SubsetsTestingTherapeuticTherapeutic UsesThymus GlandTissue PreservationTissuesUnited States National Institutes of HealthWild Type MouseWorkZAP-70 Genebasebiophysical propertiesclinical applicationcytokinehuman diseaseimmunological interventionimmunoreactionimmunoregulationimprovedin vivoinnovationinsightnovel strategiespathogenpreventprogenitorprogramsresponse
项目摘要
Project Summary
Invariant Natural Killer T (iNKT) cells play a central role in several immune responses in diverse biological
contexts ranging from autoimmunity, injury and infections to pregnancy and metabolic disease as well as
cancer. iNKT cells are characterized by their use of a very limited T cell antigen receptor (TCR) repertoire to
recognize lipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like
antigen-presenting molecule. A number of functionally distinct iNKT cell subpopulations, each with propensity
to traffic to different tissues and to secrete different cytokines upon activation, have been defined. Although it is
clear that these fate assignments are conferred upon iNKT cells during selection in the thymus, the
environmental cues that direct these decisions are unknown. Our preliminary data show that 1) in wildtype
mice, the avidity of the iNKT TCR correlates with iNKT cell subsets and the expression of markers reflecting
strength of signaling during selection; 2) the development of iNKT cells in mice with a fixed TCR repertoire is
affected similarly on different genetic backgrounds; 3) the V usage and CDR3 sequences are unique to each
iNKT cell subset; 4) signaling and gene expression in the earliest definable stage of iNKT cell development,
immediately after engagement of the TCR by natural ligands in vivo, is altered in mice with reduced TCR
signaling. These mice also exhibit a cell intrinsic defect in development of iNKT cell subsets. Based on these
preliminary studies, we hypothesize that iNKT cell differentiation and function is determined by TCR specificity
and signal strength. This hypothesis will be tested by pursuing the following specific aims: 1) Determine the
basis for strain differences in thymic iNKT subset composition; 2) Determine the effect of affinity and ligand-
specificity of the TCR on development of iNKT cell subsets. The proposal is innovative because it directly
explores the role of TCR specificity/affinity for self-ligands in specifying the development of iNKT cell subsets.
The proposed research is significant because it will inform our understanding of iNKT cell subset development
and dynamics, a pre-requisite to immune intervention aimed at manipulating and optimizing iNKT cell-based
therapies.
项目摘要
不变的自然杀伤T(iNKT)细胞在多种生物学中的几种免疫应答中发挥核心作用。
从自身免疫、损伤和感染到妊娠和代谢疾病,
癌iNKT细胞的特征在于它们使用非常有限的T细胞抗原受体(TCR)库,
识别由CD 1d呈递的脂质抗原,CD 1d是一种非多态性的I类主要组织相容性复合物,
抗原呈递分子许多功能不同的iNKT细胞亚群,每个亚群都有倾向性
运输到不同的组织并在激活后分泌不同的细胞因子。虽然
显然,这些命运分配是在胸腺选择过程中赋予iNKT细胞的,
指导这些决定的环境线索是未知的。我们的初步数据显示,1)在野生型中,
在小鼠中,iNKT TCR的亲合力与iNKT细胞亚群和反映免疫应答的标志物的表达相关。
选择过程中的信号强度; 2)具有固定TCR库的小鼠中iNKT细胞的发育是
在不同的遗传背景下受到类似的影响; 3)V基因的使用和CDR 3基因序列对每个基因都是独特的
iNKT细胞亚群; 4)iNKT细胞发育的最早可定义阶段中的信号传导和基因表达,
在TCR与体内天然配体结合后,在TCR减少的小鼠中立即发生改变
信号这些小鼠在iNKT细胞亚群的发育中也表现出细胞内在缺陷。基于这些
在初步研究中,我们假设iNKT细胞的分化和功能是由TCR特异性决定的,
和信号强度。这一假设将通过追求以下具体目标来检验:1)确定
胸腺iNKT亚群组成的菌株差异的基础; 2)确定亲和力和配体的影响,
TCR对iNKT细胞亚群发育的特异性。该提案具有创新性,因为它直接
探索了TCR对自身配体的特异性/亲和力在指定iNKT细胞亚群的发育中的作用。
这项拟议的研究意义重大,因为它将为我们了解iNKT细胞亚群的发育提供信息。
和动力学,免疫干预的先决条件,旨在操纵和优化iNKT细胞为基础的
治疗
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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Laurent Gapin其他文献
Laurent Gapin的其他文献
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{{ truncateString('Laurent Gapin', 18)}}的其他基金
Transcriptional Regulation of Innate T cell fate
先天 T 细胞命运的转录调控
- 批准号:
10450153 - 财政年份:2021
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$ 38.16万 - 项目类别:
Transcriptional Regulation of Innate T cell fate
先天 T 细胞命运的转录调控
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10283893 - 财政年份:2021
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Role of MAIT cells in a mouse model of spontaneous colitis
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Genetic determinants of "innate" T lymphocytes development and homeostasis
“先天”T 淋巴细胞发育和稳态的遗传决定因素
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10412121 - 财政年份:2021
- 资助金额:
$ 38.16万 - 项目类别:
Role of MAIT cells in a mouse model of spontaneous colitis
MAIT细胞在自发性结肠炎小鼠模型中的作用
- 批准号:
10300940 - 财政年份:2021
- 资助金额:
$ 38.16万 - 项目类别:
Genetic determinants of "innate" T lymphocytes development and homeostasis
“先天”T 淋巴细胞发育和稳态的遗传决定因素
- 批准号:
10251641 - 财政年份:2021
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TCR signal strength and iNKT cell subset development
TCR 信号强度和 iNKT 细胞亚群发育
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10447807 - 财政年份:2018
- 资助金额:
$ 38.16万 - 项目类别:
TCR signal strength and iNKT cell subset development
TCR 信号强度和 iNKT 细胞亚群发育
- 批准号:
9761964 - 财政年份:2018
- 资助金额:
$ 38.16万 - 项目类别:
TCR signal strength and iNKT cell subset development
TCR 信号强度和 iNKT 细胞亚群发育
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10219060 - 财政年份:2018
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mCD1D2 在 iNKT 细胞发育和功能中的作用
- 批准号:
9431944 - 财政年份:2018
- 资助金额:
$ 38.16万 - 项目类别:
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