Regulation of alveolar epithelial regeneration by T cells

摘要 肺实质中的肺泡上皮在保护肺免受吸入颗粒物/化学品的伤害中起着关键作用。 和呼吸道感染。因此，肺泡上皮的再生能力是恢复的关键。 以重建上皮屏障，恢复肺功能。肺泡上皮 由肺泡上皮I型细胞(AECI)和肺泡II型细胞(AECII)组成。续签 AECI被认为依赖于AECII，即分化为AECI的肺泡上皮祖细胞。 因此，AECII在肺泡上皮对损伤的快速再生中是必不可少的。 已知宿主免疫反应可在细菌性肺炎期间引起肺损伤，并可能在 规范修复和再生。我们已经发现了T细胞在调节 AECII在细菌性肺炎肺损伤修复中的分化能力。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小鼠感染了 与肺炎链球菌T4株(SpT4)，社区获得性肺炎最常见的病原体 肺炎，仅在肺实质受损，AECI和AECII丢失并增加 免疫细胞的渗入。其次是通过分化前牙槽上皮细胞再生肺泡上皮。 现有的表面活性蛋白C(SPC)-表达AECII。AECII到AECI差异化的增加 与AECII中YAP和TAZ核蛋白水平的上调及T的快速分解有关 肺泡内的细胞。缺乏AECII特异性YAP/Taz的小鼠表现出AECII到AECI的减少 分化，表明YAP/Taz在AECII分化中起重要作用。此外，我们发现， 当AECII与CD4或CD8 T细胞共同培养时，AECII向AECI的分化受到显著抑制 在体外的小鼠和人类模型系统中。SpT4致小鼠肺损伤后，持续性T细胞 肺泡的反应对AECII向AECI的分化有显著的抑制作用，并使肺泡减少 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核来实现的 AECII的活动。基于这些初步研究，中心假设是持续性的CD4/CD8 T细胞 RESPONSE通过下调AECII的YAP/Taz核活性，抑制AECII的分化能力。 旨在加速肺内CD4/CD8 T细胞分解的免疫调节策略将促进 AECII向AECI分化与肺泡上皮再生 这项建议旨在通过以下方式确定CD4/CD8T细胞在调节AECII功能中的机制作用 CD4/CD8 T细胞调节AECII向AECI分化机制的研究 实验性细菌性肺炎小鼠模型及AECII与T细胞亚群体外共培养体系的建立 从人类和老鼠身上。我们还将研究T细胞疗法在促进AECII到AECI方面的潜力 一种动物模型的分化和肺泡上皮再生。

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.