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.

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CpG) award. M.T.W. is supported by the NIH (grant no. R01 NS099068), a Cincinnati Children's Research Foundation Endowed Scholar Award, and a CCHMC CpG award. M.E.R.'s work is funded by the NIH (grant nos. R37 AI045898, U19 AI070235, R01 AI057803, R01 HG010730, and R01 AR073228); the Campaign Urging Research for Eosinophilic Disease; and the Sunshine Charitable Foundation and its supporters, Denise and David Bunning. This study was originally funded by the Consortium of Food Allergy Researchers (COFAR, National Institute of Allergy and Infectious Diseases grant no. U19AI066738). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Disclosure of potential conflict of interest: V. Mukkada is a consultant for Shire, a Takeda company. T. Wen is a coinventor of the EoE diagnostic panel, a patent owned by Cincinnati Children's Hospital Medical Center, and serves as a consultant for NanoString Technologies, Inc, and a consultant committee member for GlaxoSmithKline. M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celgene, Astra Zeneca, Arena Pharmaceuticals, Guidepoint, and Suvretta Capital Management; has an equity interest in the first 5 listed and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children's Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest.

Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.