Understand the molecular mechanism of age-associated decline in antiviral CD8 T cell immunity
了解与年龄相关的抗病毒 CD8 T 细胞免疫力下降的分子机制
基本信息
- 批准号:10726485
- 负责人:
- 金额:$ 20.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAgeAgingAntigensApoptosisBindingBinding SitesBiological AssayCD8-Positive T-LymphocytesCell LineageCellsCellular Metabolic ProcessCessation of lifeChromatinChronicCommunicable DiseasesCoronavirus InfectionsDataDefectDevelopmentElderlyEpigenetic ProcessEquilibriumFlow CytometryFrequenciesFutureGenesGenetic TranscriptionIL2 geneImmuneImmune responseImmunityImpairmentIn VitroIndividualInfectionMetabolicMetabolic PathwayMetabolismModelingMolecularMorbidity - disease rateMurine hepatitis virusMusPathway interactionsPrevalenceRoleSARS coronavirusSeveritiesSignal TransductionStimulusT cell differentiationT cell responseT-LymphocyteT-Lymphocyte SubsetsViralViral hepatitisVirusVirus DiseasesXCL1 geneage relatedagedantiviral immunityexhaustexhaustionexperimental studygenetic signatureimmunosenescenceimprovedinfluenza infectionmetabolic ratemortalitymouse modelpathogenic virusprogrammed cell death protein 1programssingle-cell RNA sequencingtranscription factortranscriptometranscriptome sequencingvaccine efficacy
项目摘要
Summary
Immunosenescence increases morbidity and mortality after infection and reduces vaccine efficacy. Most deaths
associated with infections by influenza virus, SARS-CoV, or SARS-CoV-2 occurred in people older than 65. Thus,
understanding the mechanism of age-associated decline in antiviral immunity is critical to the development of
strategies to protect the elderly from viral pathogens. Despite its critical role in protection against infections, T-
cell immunity declines with age. During aging, the prevalence of naïve T cells decreases, whereas the frequency
of terminally differentiated CD8 T cells increases. In addition, aging reduces the responsiveness of naïve T cells
to antigen. However, the molecular mechanism underlying age-associated decline in antiviral T cell immunity
remains poorly defined. Using a mouse model of murine hepatitis virus (MHV) infection, we found that aging
increased mortality and decreased antiviral CD4 and CD8 T cell responses. Surprisingly, although aging
increased terminally differentiated CD8 T cells at baseline, there was a profound reduction in terminally
differentiated effector CD8 T cells and an elevated gene-signature of T-cell exhaustion in aged mice after MHV
infection. In addition, we showed that age-associated decline in T-cell expansion was primarily caused by TCR-
triggered apoptosis and necroptosis pathways and was rescued by rebalancing TCR and IL2 signaling. We also
found that aging reduced the metabolic rate of T cells at baseline and impaired metabolic adaptation of T cells
after activation. Here, we hypothesize that age-associated exhaustion-prone epigenetic state and defective
metabolic adaptation impair effector CD8 T cell response in viral infection. In this study, we will define the
epigenetic and metabolic pathways in antiviral CD8 T cells altered by aging before and after infection, while
accounting for age-associated changes in differentiation. We will also evaluate strategies that harness IL2 and
TCR pathways to rescue age-related defects in antiviral CD8 T cells.
总结
免疫衰老增加了感染后的发病率和死亡率,降低了疫苗的效力。大多数死亡
与流感病毒、SARS-CoV或SARS-CoV-2感染相关的疾病发生在65岁以上的人群中。因此,在本发明中,
了解与年龄相关的抗病毒免疫力下降的机制对于开发抗病毒药物至关重要。
保护老年人免受病毒病原体侵害的战略。尽管它在预防感染方面发挥着关键作用,但T-
细胞免疫力随着年龄的增长而下降。在衰老过程中,幼稚T细胞的流行率下降,而频率
终末分化的CD8 T细胞增加。此外,衰老降低了幼稚T细胞的反应性。
抗原。然而,与年龄相关的抗病毒T细胞免疫力下降的分子机制
仍然定义不清。使用小鼠肝炎病毒(MHV)感染的小鼠模型,我们发现,
增加死亡率和降低抗病毒CD4和CD8 T细胞应答。令人惊讶的是,尽管衰老
基线时终末分化的CD8 T细胞增加,终末分化的CD8 T细胞显著减少。
MHV后老年小鼠中分化的效应CD8 T细胞和升高的T细胞耗竭基因特征
感染此外,我们发现,年龄相关的T细胞扩增下降主要是由TCR-1引起的。
触发细胞凋亡和坏死性凋亡途径,并通过重新平衡TCR和IL 2信号转导来挽救。我们也
发现衰老降低了T细胞在基线时的代谢率,并损害了T细胞的代谢适应
激活后。在这里,我们假设,年龄相关的耗竭倾向的表观遗传状态和缺陷
代谢适应损害病毒感染中的效应CD 8 T细胞反应。在这项研究中,我们将定义
抗病毒CD8 T细胞的表观遗传和代谢途径在感染前后因衰老而改变,
解释了与年龄相关的分化变化。我们还将评估利用IL 2和
TCR途径拯救抗病毒CD8 T细胞中的年龄相关缺陷
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)
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Tuoqi Wu其他文献
Tuoqi Wu的其他文献
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{{ truncateString('Tuoqi Wu', 18)}}的其他基金
Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection
编程干细胞样 CD8 T 细胞以增强针对慢性病毒感染的抗病毒免疫力
- 批准号:
10819055 - 财政年份:2022
- 资助金额:
$ 20.5万 - 项目类别:
Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection
编程干细胞样 CD8 T 细胞以增强针对慢性病毒感染的抗病毒免疫力
- 批准号:
10687970 - 财政年份:2022
- 资助金额:
$ 20.5万 - 项目类别:
Program stem-like CD8 T cells to enhance antiviral immunity against chronic viral infection
编程干细胞样 CD8 T 细胞以增强针对慢性病毒感染的抗病毒免疫力
- 批准号:
10365756 - 财政年份:2022
- 资助金额:
$ 20.5万 - 项目类别:
Rejuvenating aged T cell immunity by targeting stem cell-like CD8 T cells
通过靶向干细胞样 CD8 T 细胞恢复衰老 T 细胞免疫力
- 批准号:
10190752 - 财政年份:2018
- 资助金额:
$ 20.5万 - 项目类别:
Rejuvenating aged T cell immunity by targeting stem cell-like CD8 T cells
通过靶向干细胞样 CD8 T 细胞恢复衰老 T 细胞免疫力
- 批准号:
10516508 - 财政年份:2018
- 资助金额:
$ 20.5万 - 项目类别:
Rejuvenating aged T cell immunity by targeting stem cell-like CD8 T cells
通过靶向干细胞样 CD8 T 细胞恢复衰老 T 细胞免疫力
- 批准号:
10005996 - 财政年份:2018
- 资助金额:
$ 20.5万 - 项目类别:
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