Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA.
Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45219, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Immunity. 2020 Feb 18;52(2):275-294.e9. doi: 10.1016/j.immuni.2020.01.005.
Type 3 innate lymphoid cells (ILC3s) are critical for lung defense against bacterial pneumonia in the neonatal period, but the signals that guide pulmonary ILC3 development remain unclear. Here, we demonstrated that pulmonary ILC3s descended from ILC precursors that populated a niche defined by fibroblasts in the developing lung. Alveolar fibroblasts produced insulin-like growth factor 1 (IGF1), which instructed expansion and maturation of pulmonary ILC precursors. Conditional ablation of IGF1 in alveolar fibroblasts or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Premature infants with bronchopulmonary dysplasia, characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced IGF1 concentrations and pulmonary ILC3 numbers. These findings indicate that the newborn period is a critical window in pulmonary immunity development, and disrupted lung development in prematurely born infants may have enduring effects on host resistance to respiratory infections.
3 型固有淋巴细胞 (ILC3s) 对于新生儿期肺部抵御细菌性肺炎至关重要，但指导肺 ILC3 发育的信号仍不清楚。在这里，我们证明肺 ILC3 来源于在发育中的肺中由成纤维细胞定义的小生境中定植的 ILC 前体。肺泡成纤维细胞产生胰岛素样生长因子 1 (IGF1)，指导肺 ILC 前体的扩增和成熟。肺泡成纤维细胞中 IGF1 的条件性缺失或 ILC 前体中 IGF-1 受体的缺失中断了 ILC3 的发生，使新生小鼠易患肺炎。支气管肺发育不良的早产儿，其特征是出生后肺泡发育中断和呼吸道感染发病率增加，IGF1 浓度和肺 ILC3 数量减少。这些发现表明新生儿期是肺部免疫发育的关键窗口期，早产儿肺部发育中断可能对宿主抵抗呼吸道感染产生持久影响。
