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
• 负责人: Beata Kosmider
• 金额: $ 55.48万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556409
• 关键词: Acceleration; Affect; Alveolar; Alveolar Cell Type I; Animal Model; Animals; Antigen-Antibody Complex; Bacterial Pneumonia; Biological Models; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Chemicals; Coculture Techniques; Down-Regulation; Ensure; Epithelial Cells; Epithelium; Exhibits; Flow Cytometry; Gases; Genetic; Human; Immune response; In Vitro; Infection; Inflammatory Response; Inhalation; Injury; Interferon Type II; Interleukin-1 beta; Lung; Lung infections; Mediating; Modeling; Monoclonal Antibodies; Mus; Natural regeneration; Nuclear; Nuclear Protein; Patients; Play; Predisposition; Process; Proliferating; Pulmonary Inflammation; Pulmonary Surfactant-Associated Protein C; Pulmonary alveolar structure; Recovery; Regenerative capacity; Regulation; Resolution; Respiratory Tract Infections; Role; Streptococcus pneumoniae; Structure of parenchyma of lung; Surface; System; T cell regulation; T cell response; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Type II Epithelial Receptor Cell; Up-Regulation; adaptive immune response; alveolar epithelium; alveolar type II cell; community acquired pneumonia; cytokine; epithelial stem cell; epithelium regeneration; gain of function; genetic approach; human model; immune cell infiltrate; immunopathology; immunoregulation; in vivo; lung injury; lung regeneration; lung repair; mouse model; novel therapeutic intervention; particle; pathogen; pharmacologic; prevent; progenitor; pulmonary function; repaired; response; response to injury

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

Impaired Alveolar Re-Epithelialization in Pulmonary Emphysema.

• DOI: 10.3390/cells11132055
• 发表时间: 2022-06-28
• 期刊: Cells
• 影响因子: 6

CD8 T cell response and its released cytokine IFN-γ are necessary for lung alveolar epithelial repair during bacterial pneumonia.

• DOI: 10.3389/fimmu.2023.1268078
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Zhang, Xiaoying;Ali, Mir;Pantuck, Morgan Alexandra;Yang, Xiaofeng;Lin, Chih-Ru;Bahmed, Karim;Kosmider, Beata;Tian, Ying
• 通讯作者: Tian, Ying

Expression of SARS-CoV-2 Entry Factors in Human Alveolar Type II Cells in Aging and Emphysema.

• DOI: 10.3390/biomedicines9070779
• 发表时间: 2021-07-06
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Lin CR;Bahmed K;Simborio H;Hayek H;Bolla S;Marchetti N;Criner GJ;Kosmider B
• 通讯作者: Kosmider B

Transcriptional responses to injury of regenerative lung alveolar epithelium.

• DOI: 10.1016/j.isci.2022.104843
• 发表时间: 2022-08-19
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Ali, Mir;LaCanna, Ryan;Lian, Zhaorui;Huang, Jian;Tan, Yinfei;Shao, Wenna;Yu, Xiang;Tian, Ying
• 通讯作者: Tian, Ying