Tissue niches for ILC3 development in newborn's lung

项目概要： 细菌性肺炎每年在全世界造成100多万婴儿死亡。3型先天性 淋巴样细胞（ILC3）对于肺粘膜防御细菌性肺炎是至关重要的， 新生儿然而，指导肺ILC3发生的信号并不完全， 明白一波ILC3在出生后第一周内积聚到新生儿肺部 与出生后肺生长和肠道微生物群定植同时发生。临床 例如，对早产儿的干预，抗生素的使用改变了微生物群， 与肺ILC3减少和肺炎风险增加有关。同样，治疗方法，如 机械通气和皮质类固醇中断了出生后的肺生长， 支气管肺发育不良（BPD）。患有BPD的婴儿肺ILC3降低， 由于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+基质细胞亚群密切相关，产生肺ILC3 利基胰岛素样生长因子（IGF）1是肺ILC3生态位的重要组成部分。我们 发现在小生境细胞中运作的发育信号指示分化， 肺ILC3的功能适应性。出生后肺生长和定植的收敛， 新生儿时期“关键窗口”期间的肠道微生物群允许发育中的肺 和不断进化的微生物群来“指导”迅速成熟的肺粘膜防御。此种趋同 确保对呼吸道病原体的持久保护。我们假设， 来自细菌的信号与发育程序化的线索合作， 独特的肺部小生境来塑造肺部的免疫环境。拟议的研究将解决 以下关于肺ILC3发育的知识空白。1)什么时候是肺ILC3龛 如何在整个童年时期保持这种能力（目标1）？2)如何 ILC3生态位指导肺ILC3的发育、分化和功能适应性（目的2）？第三章 肺生态位如何整合来自肠道细菌的信号（目标3）？ 总之，这些目标将使用适合发展的模型来回答一个重要的和未知的问题。 问题：新生儿的肺部如何接种ILC3，以及它们如何在肺部小生境中受到调节 通过局部和肺外输入。

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.