Metabolic Regulation of CD8 T Cell Memory Development
CD8 T 细胞记忆发育的代谢调节
基本信息
- 批准号:8452685
- 负责人:
- 金额:$ 35.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-11-01 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAddressAntigensBacterial AntigensBacterial InfectionsBiochemicalCD8B1 geneCatabolic ProcessCatabolismCellsCellular ImmunityChronicCitric Acid CycleCommunicable DiseasesDataDefectDevelopmentDiseaseFDA approvedFailureFamilyGenerationsGenesGeneticGoalsImmune responseImmunityImmunologic MemoryImmunotherapyInfectionInterleukin-1JournalsLifeLinkLipidsMaintenanceMalignant NeoplasmsMemoryMetabolicMetabolismMetforminMitochondriaMolecularMusNaturePathway interactionsPharmaceutical PreparationsPhasePlayPopulationProcessPublic HealthPublishingRegulationRoleSignal TransductionSirolimusT cell responseT memory cellT-Cell DevelopmentT-LymphocyteTestingTherapeuticTimeTumor Necrosis Factor ReceptorVaccinationadapter proteinbasefatty acid metabolismfatty acid oxidationgain of functionimprovedin vivoinstrumentationloss of functionmouse modelnovelpathogenprogramspublic health relevanceresearch studyresponsetoolvaccine efficacy
项目摘要
DESCRIPTION (provided by applicant): Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. CD8 T cells play a crucial role in immunity to infections with intracellular pathogens. Upon stimulation, these T cells undergo a developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of antigen-specific effector T cell populations, followed by the persistence of long-lived memory T cells that mediate immunity to re-infection. The mechanisms underlying the generation and maintenance of memory CD8 T cells remain unclear. Previously we demonstrated that mice lacking Traf6 (a TNFR and IL-1/TLR family adapter protein) in T cells mount effector CD8 T cell responses to infection, but are unable to establish memory CD8 T cells. Our experiments revealed that this CD8 T cell intrinsic failure of memory development was tightly linked to the inability of Traf6-deficient CD8 T cells to initiate mitochondrial fatty acid oxidation, a pathway of lipid catabolism that fuels the TCA cycle. Based on our observations, and a panel of supportive preliminary data, we hypothesize that catabolic processes of energy generation are essential for the development of memory CD8 T cells after infection and that Traf6 plays a key role regulating this process. We will test this hypothesis through the following specific aims: 1) Determine how fatty acid metabolism regulates memory CD8 T cell development; 2) Determine the extent of Traf6-dependent regulation of memory CD8 T cell development; and 3) Establish that pharmacological manipulation of CD8 T cell metabolism can be therapeutic. The long-term goal of these studies is to facilitate the development of immunotherapies against infectious diseases.
免疫记忆是疫苗接种的基础,这可能是当今最重要的公共卫生工具。CD 8 T细胞在对细胞内病原体感染的免疫中起着至关重要的作用。在刺激后,这些T细胞经历发育程序,其特征在于不同的阶段,包括抗原特异性效应T细胞群体的首先扩增,然后收缩,随后是介导对再感染的免疫力的长寿命记忆T细胞的持续存在。记忆性CD 8 T细胞的产生和维持机制尚不清楚。先前我们证明了T细胞中缺乏Traf 6(TNFR和IL-1/TLR家族衔接蛋白)的小鼠对感染产生效应CD 8 T细胞应答,但不能建立记忆CD 8 T细胞。我们的实验表明,这种CD 8 T细胞记忆发育的内在失败与Traf 6缺陷的CD 8 T细胞无法启动线粒体脂肪酸氧化密切相关,这是一种为TCA循环提供燃料的脂质催化剂途径。基于我们的观察和一组支持性的初步数据,我们假设能量产生的分解代谢过程对于感染后记忆性CD 8 T细胞的发育是必不可少的,Traf 6在调节这一过程中起着关键作用。我们将通过以下具体目标来检验这一假设:1)确定脂肪酸代谢如何调节记忆性CD 8 T细胞发育; 2)确定Traf 6依赖性调节记忆性CD 8 T细胞发育的程度; 3)确定CD 8 T细胞代谢的药理学操纵可以是治疗性的。这些研究的长期目标是促进针对感染性疾病的免疫疗法的发展。
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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Erika L Pearce其他文献
Erika L Pearce的其他文献
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TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
肿瘤对 T 细胞施加的葡萄糖限制会削弱免疫力
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8913080 - 财政年份:2014
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TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
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9337389 - 财政年份:2014
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TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
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9151813 - 财政年份:2014
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$ 35.72万 - 项目类别:
TUMOR-IMPOSED GLUCOSE RESTRICTIONS ON T CELLS DAMPEN IMMUNITY
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Metabolic Regulation of CD8 T Cell Memory Development
CD8 T 细胞记忆发育的代谢调节
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- 资助金额:
$ 35.72万 - 项目类别:
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