Tissue niches for ILC3 development in newborn's lung

项目总结： 细菌性肺炎每年导致全球100多万名婴儿死亡。先天类型3 淋巴样细胞(ILC3)在细菌性肺炎的肺粘膜防御中起关键作用。 新生儿。然而，指导肺ILC3s发展的信号是不完全的 明白了。在出生的第一周，ILC3的浪潮积聚到新生儿的肺中 与出生后的肺生长和共生微生物群的定植同步。临床 对早产儿的干预，例如，抗生素的使用改变了微生物区系，并 与肺内ILC3降低和肺炎风险增加有关。同样，像这样的疗法 机械通气和皮质类固醇干扰出生后肺生长，导致 支气管肺发育不良(BPD)。BPD患儿肺ILC3降低，ILC3升高 因呼吸道感染而发病的可能性。因此，理解这种关系是 临床上很重要。在已发表的研究中，我们发现ILC3定位于新生儿的肺泡 肺，在那里它们与Gli1基质细胞的子集密切相关，形成肺ILC3 利基市场。胰岛素样生长因子(IGF)1是肺ILC3生态位的重要组成部分。我们 研究发现，在壁龛细胞中运行的发育信号指导分化和 肺ILC3的功能适合性。出生后肺生长和定植的会聚 新生儿期“关键窗口期”的共生微生物群使发育中的肺 以及进化的微生物区系，以“指导”迅速成熟的肺粘膜防御。这样的趋同 确保对呼吸道病原体的持久保护。我们假设精心安排的时间 来自共生细菌的信号与发育编程的线索协同作用 独特的肺脏壁龛，可在肺部形成免疫环境。拟议的研究将解决 关于肺ILC3发育的以下知识差距。1)肺ILC3的生态位是什么时候 如何在整个童年期间保持这种天赋(目标1)？2)如何 ILC3生态位指导肺ILC3的发育、分化和功能适应(目标2)？3 肺部生态位如何整合来自共生细菌的信号(目标3)？ 总而言之，这些目标将使用适合发展的模型来回答一个重要和未知的问题 问：新生儿的肺是如何接种ILC3的，它们在肺脏的壁龛是如何调节的 通过局部和肺外输入贯穿整个童年。

PROJECT SUMMARY : Bacterial pneumonia kills more than one million infants around the world each year. Type 3 innate lymphoid cells (ILC3) are critical for lung mucosal defense against bacterial pneumonia in the newborns. However, the signals that guide pulmonary ILC3s development are incompletely understood. A wave of ILC3s accumulate into the newborn lungs during the first week of life contemporaneous with postnatal lung growth and colonization by commensal microbiota. Clinical interventions in premature infants, for instance, the use of antibiotics alter microbiota and are associated with decreased lung ILC3s and increased risk of pneumonia. Similarly, therapies such as mechanical ventilation and corticosteroids interrupt the postnatal lung growth leading to bronchopulmonary dysplasia (BPD). Infants with BPD have decreased lung ILC3 and increased likelihood of morbidity due to respiratory infections. Therefore, understanding this relationship is clinically important. In published studies, we found that ILC3s localized to the alveoli in the newborn lungs, where they intimately associated with a subset of Gli1+ stromal cells creating a pulmonary ILC3 niche. Insulin-like growth factor (IGF)1 was an essential component of the pulmonary ILC3 niche. We found that developmental signals operating in the niche cells instructed the differentiation and functional fitness of lung ILC3. The convergence of postnatal lung growth and colonization by commensal microbiota during the `critical window' of the newborn period allows the developing lung and evolving microbiota to `instruct' rapidly maturing pulmonary mucosal defenses. Such convergence ensures long-lasting protection against respiratory pathogens. We hypothesize that carefully timed signals from commensal bacteria act cooperatively with developmentally programmed cues in the unique lung niches to pattern the immune environment in the lung. The proposed studies will resolve the following knowledge gaps regarding lung ILC3 development. 1) When is the lung ILC3 niche endowed during development and how is it maintained throughout childhood (Aim 1)? 2) How does ILC3 niche instruct the development, differentiation and functional fitness of lung ILC3 (Aim 2) ? 3) How does the lung niche integrate the signals from commensal bacteria (Aim 3)? Together, these aims will use developmentally appropriate models to answer a vital and unknown question: how the newborn's lungs are seeded with ILC3 and how they are regulated at their lung niches via local and extrapulmonary inputs throughout childhood.