Regulation of alveolar epithelial regeneration by T cells
T 细胞对肺泡上皮再生的调节
基本信息
- 批准号:10323010
- 负责人:
- 金额:$ 55.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlveolarAnimal ModelAnimalsAntigen-Antibody ComplexBacterial PneumoniaBiological ModelsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell Differentiation processCell physiologyCellsChemicalsCoculture TechniquesDown-RegulationEnsureEpithelialEpithelial CellsExhibitsFlow CytometryGasesGeneticHumanImmune responseIn VitroInfectionInflammatory ResponseInhalationInjuryInterferon Type IIInterleukin-1 betaLungLung infectionsMediatingModelingMonoclonal AntibodiesMusNatural regenerationNuclearNuclear ProteinPatientsPharmacologyPlayProcessProliferatingPulmonary InflammationPulmonary Surfactant-Associated Protein CPulmonary alveolar structureRecoveryRegenerative capacityRegulationResolutionRespiratory Tract InfectionsRoleStreptococcus pneumoniaeStructure of parenchyma of lungSurfaceSystemT cell regulationT cell responseT cell therapyT-LymphocyteT-Lymphocyte SubsetsTechniquesTestingTimeTumor-infiltrating immune cellsType I Epithelial Receptor CellType II Epithelial Receptor CellUp-Regulationadaptive immune responsealveolar epitheliumbasecommunity acquired pneumoniacytokineepithelial stem cellepithelium regenerationgain of functiongenetic approachhuman modelimmunopathologyimmunoregulationin vivoinjury and repairlung injurylung regenerationlung repairmouse modelnovel therapeutic interventionparticlepathogenpreventprogenitorpulmonary functionrepairedresponseresponse to injury
项目摘要
SUMMARY
Alveolar epithelium in lung parenchyma plays a pivotal role in protecting lung from inhaled particles/chemicals
and respiratory infections. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery
from these insults in order to rebuild the epithelial barrier and restore pulmonary functions. Alveolar epithelium
is composed of alveolar epithelial type I cells (AECI) and alveolar epithelial type II cells (AECII). The renewal of
AECI is considered to be depend on AECII, the alveolar epithelial progenitor cells, which differentiate into AECI.
Thus AECII are essential in the rapid regeneration of the alveolar epithelium in response to injury.
Host immune responses are known to cause lung injury during bacterial pneumonia and may also play a role in
regulating repair and regeneration. we have uncovered a previously unrecognized role of T cells on regulating
AECII differentiation capacity during bacterial pneumonia-induced lung injury and repair. Using a combination
of genetic lineage tracing, flow cytometry, and immunostaining, our preliminary studies show that mice infected
with Streptococcus pneumonia Strain T4 (SpT4), the most common pathogen of community-acquired
pneumonia, had injuries exclusively in the lung parenchyma, with loss of AECI and AECII and increased
infiltration of immune cells. This was followed by alveolar epithelial regeneration via differentiation of pre-
existing Surfactant Protein C (SPC)- expressing AECII into AECI. This increase in AECII-to-AECI differentiation
was correlated with up-regulation of nuclear protein levels of Yap and Taz in AECII and rapid resolution of T
cells in lung alveoli. Mice that lacked Yap/Taz specifically in AECII exhibited diminished AECII-to-AECI
differentiation, indicating the essential role of Yap/Taz in AECII differentiation. Furthermore, we found that
AECII-to-AECI differentiation was substantially inhibited when AECII were co-cultured with CD4 or CD8 T cells
in both murine and human model systems in vitro. After SpT4-induced lung injury in mice, persistent T-cell
response in lung alveoli caused dramatic inhibition on AECII-to-AECI differentiation and decreased alveolar
epithelial regeneration. We identified that CD4/CD8 T cells functioned, in part, by suppressing Yap/Taz nuclear
activity in AECII. Based on these preliminary studies, the central hypothesis is that persistent CD4/CD8 T-cell
response inhibits AECII differentiation capacity through down-regulation of Yap/Taz nuclear activity in AECII.
Immunomodulatory strategies aimed at accelerating resolution of CD4/CD8 T cells in the lung will promote
AECII-to-AECI differentiation and alveolar epithelial regeneration.
This proposal aims to define the mechanistic role of CD4/CD8 T cells in regulating AECII function by
investigating the mechanisms underlying CD4/CD8 T-cell regulation on AECII-to-AECI differentiation in an
experimental bacterial pneumonia mouse model, and an in vitro co-culture system of AECII with T-cell subset
from both human and mouse. We will also examine the potential of T-cell therapy in promoting AECII-to-AECI
differentiation and alveolar epithelial regeneration in an animal model.
概括
肺实质中的肺泡上皮在保护肺部免受吸入颗粒/化学物质侵害方面发挥着关键作用
和呼吸道感染。因此,肺泡上皮的再生能力对于恢复至关重要
免受这些损伤,以重建上皮屏障并恢复肺功能。肺泡上皮
由肺泡上皮I型细胞(AECI)和肺泡上皮II型细胞(AECII)组成。的更新
AECI被认为依赖于AECII,即肺泡上皮祖细胞,其分化为AECI。
因此,AECII 对于肺泡上皮响应损伤的快速再生至关重要。
众所周知,宿主免疫反应会在细菌性肺炎期间引起肺损伤,并且也可能在以下方面发挥作用:
调节修复和再生。我们发现了 T 细胞在调节中以前未被认识到的作用
细菌性肺炎引起的肺损伤和修复过程中 AECII 的分化能力。使用组合
通过遗传谱系追踪、流式细胞术和免疫染色,我们的初步研究表明,感染的小鼠
肺炎链球菌 T4 株 (SpT4),社区获得性肺炎最常见的病原体
肺炎,仅肺实质损伤,AECI 和 AECII 丧失,并且增加
免疫细胞的浸润。随后通过前体细胞的分化进行肺泡上皮再生。
将现有的表面活性蛋白 C (SPC)-表达 AECII 转化为 AECI。 AECII 到 AECI 分化的增加
与 AECII 中 Yap 和 Taz 核蛋白水平的上调以及 T 的快速消退相关
肺泡中的细胞。 AECII 中特别缺乏 Yap/Taz 的小鼠表现出 AECII 至 AECI 的减少
分化,表明 Yap/Taz 在 AECII 分化中的重要作用。此外,我们发现
当 AECII 与 CD4 或 CD8 T 细胞共培养时,AECII 向 AECI 的分化受到显着抑制
在体外小鼠和人类模型系统中。 SpT4 诱导小鼠肺损伤后,持续性 T 细胞
肺泡反应对 AECII 到 AECI 的分化产生显着抑制并减少肺泡
上皮再生。我们发现 CD4/CD8 T 细胞的功能部分是通过抑制 Yap/Taz 核来发挥作用的。
AECII 中的活动。基于这些初步研究,中心假设是持久性 CD4/CD8 T 细胞
反应通过下调 AECII 中的 Yap/Taz 核活性来抑制 AECII 分化能力。
旨在加速肺部 CD4/CD8 T 细胞分辨率的免疫调节策略将促进
AECII 至 AECI 分化和肺泡上皮再生。
该提案旨在通过以下方式定义 CD4/CD8 T 细胞在调节 AECII 功能中的机制作用:
研究 CD4/CD8 T 细胞对 AECII 至 AECI 分化的调节机制
实验性细菌性肺炎小鼠模型以及AECII与T细胞亚群的体外共培养系统
来自人类和小鼠。我们还将研究 T 细胞疗法在促进 AECII 至 AECI 方面的潜力
动物模型中的分化和肺泡上皮再生。
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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Beata Kosmider其他文献
Beata Kosmider的其他文献
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{{ truncateString('Beata Kosmider', 18)}}的其他基金
Alveolar Epithelial Cell Dysfunction Induced By Flavored E-Cigarette Aerosols
加味电子烟气雾剂引起的肺泡上皮细胞功能障碍
- 批准号:
10770080 - 财政年份:2023
- 资助金额:
$ 55.48万 - 项目类别:
Alveolar epithelial cell dysfunction induced by flavored e-cigarette aerosols
加香电子烟气雾剂引起的肺泡上皮细胞功能障碍
- 批准号:
10259708 - 财政年份:2020
- 资助金额:
$ 55.48万 - 项目类别:
Alveolar epithelial cell dysfunction induced by flavored e-cigarette aerosols
加香电子烟气雾剂引起的肺泡上皮细胞功能障碍
- 批准号:
10475678 - 财政年份:2020
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of alveolar epithelial regeneration by T cells
T 细胞对肺泡上皮再生的调节
- 批准号:
10556409 - 财政年份:2020
- 资助金额:
$ 55.48万 - 项目类别:
Regulation of alveolar epithelial regeneration by T cells
T 细胞对肺泡上皮再生的调节
- 批准号:
10077891 - 财政年份:2020
- 资助金额:
$ 55.48万 - 项目类别:
Alveolar epithelial cell dysfunction induced by flavored e-cigarette aerosols
加香电子烟气雾剂引起的肺泡上皮细胞功能障碍
- 批准号:
10046451 - 财政年份:2020
- 资助金额:
$ 55.48万 - 项目类别:
DJ-1 pathway impairment in alveolar type II cells in emphysema.
肺气肿中肺泡 II 型细胞的 DJ-1 通路损伤。
- 批准号:
9108997 - 财政年份:2014
- 资助金额:
$ 55.48万 - 项目类别:
DJ-1 pathway impairment in alveolar type II cells in emphysema.
肺气肿中肺泡 II 型细胞的 DJ-1 通路损伤。
- 批准号:
9231192 - 财政年份:2014
- 资助金额:
$ 55.48万 - 项目类别:
DJ-1 pathway impairment in alveolar type II cells in emphysema.
肺气肿中肺泡 II 型细胞的 DJ-1 通路损伤。
- 批准号:
8696718 - 财政年份:2014
- 资助金额:
$ 55.48万 - 项目类别:
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