Regulation of alveolar epithelial regeneration by T cells

T 细胞对肺泡上皮再生的调节

• 批准号: 10323010
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323010
• 关键词: Affect; Alveolar; 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; Epithelial Cells; 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; Pharmacology; Play; 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; Time; Tumor-infiltrating immune cells; Type I Epithelial Receptor Cell; Type II Epithelial Receptor Cell; Up-Regulation; adaptive immune response; alveolar epithelium; base; community acquired pneumonia; cytokine; epithelial stem cell; epithelium regeneration; gain of function; genetic approach; human model; immunopathology; immunoregulation; in vivo; injury and repair; lung injury; lung regeneration; lung repair; mouse model; novel therapeutic intervention; particle; pathogen; 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免受吸入颗粒/化学物质中起关键作用 和呼吸道感染。因此，牙槽上皮的再生能力对于恢复至关重要 从这些侮辱中重建上皮屏障并恢复肺功能。牙槽上皮 由牙槽上皮I型细胞（AECI）和肺泡上皮II型细胞（AECII）组成。续约 AECI被认为取决于AECII，肺泡上皮祖细胞，该细胞分化为AECI。 因此，AECII对于响应损伤的肺泡上皮的快速再生至关重要。 已知宿主免疫反应会在细菌性肺炎期间造成肺损伤，也可能在 调节修复和再生。我们发现了T细胞在调节调节方面的先前未识别的作用 细菌性肺炎引起的肺损伤和修复过程中的AECII分化能力。使用组合 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，小鼠感染了 与肺炎链球菌菌株T4（SPT4），社区获得的最常见病原体 肺炎，仅在肺实质中受伤，损失AECI和AECII并增加 免疫细胞的浸润。接下来是通过分化的牙槽上皮再生 现有的表面活性剂蛋白C（SPC） - 将AECII表示为AECI。 AECII到AECI差异的增加 与AECII中YAP和TAZ的核蛋白水平的上调有关，T 肺肺泡中的细胞。在AECII中缺少YAP/TAZ的小鼠表现出AECII至AECI的降低 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到AECI的分化被显着抑制 在体外的鼠和人类模型系统中。 SPT4诱导小鼠肺损伤后，持续的T细胞 肺肺泡的反应引起对AECII到AECI分化的巨大抑制，并减少肺泡 上皮再生。我们确定CD4/CD8 T细胞部分通过抑制YAP/TAZ核能发挥作用 AECII的活动。基于这些初步研究，中心假设是持续的CD4/CD8 T细胞 反应通过下调AECII中的YAP/TAZ核活动来抑制AECII的分化能力。 旨在加速肺中CD4/CD8 T细胞分辨率的免疫调节策略将促进 AECII到AECI的分化和肺泡上皮再生。 该建议旨在确定CD4/CD8 T细胞在调节AECII功能中的机理作用 研究CD4/CD8 T细胞在AECII到AECI分化的机制 实验性细菌肺炎小鼠模型和AECII的体外共培养系统与T细胞子集 来自人类和老鼠。我们还将研究T细胞疗法在促进AECII到AECI方面的潜力 动物模型中的分化和牙槽上皮再生。