Bacterial pneumonia kills more than a million infants worldwide each year. Type 3 innate lymphoid cells (ILC3) are critical for lung mucosal defense against bacterial pneumonia in the neonatal period when T-cell mediated immunity is weak. The signals that guide the development of pulmonary ILC3 remain incompletely understood. Bone marrow-derived ILC3 are proposed to populate the lungs. We demonstrate that neonatal lung is the principal site of pulmonary ILC3 biogenesis. Mature pulmonary ILC3 are derived from ILC precursors that populate a spatially distinct niche, defined by fibroblasts in developing alveoli. Insulin-like growth factor (IGF) 1, produced by alveolar fibroblasts, instructed expansion and maturation of pulmonary ILC precursors throughout infancy. Conditional ablation of IGF1 in alveolar fibroblasts during postnatal development or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Finally, we show that developmental signals active in alveolar fibroblasts link the postnatal lung development with the expansion and maturation of pulmonary ILC3s, thus coordinating the simultaneous development of lungs and pulmonary mucosal defenses. Accordingly, premature infants with bronchopulmonary dysplasia, a disorder characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced levels of IGF1 and pulmonary ILC3. These data highlight the importance of newborn period as ‘critical window’ in the development of pulmonary mucosal immunity and explain why disrupted lung development in prematurely born infants has an enduring effect on host resistance to respiratory infections.
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