Immature mucosal defenses contribute to increased susceptibility of newborn infants to pathogens. Sparse knowledge of age-dependent changes in mucosal immunity has hampered improvements in neonatal morbidity due to infections. Here, we report that exposure of neonatal mice to commensal bacteria immediately after birth is required for a robust host defense against bacterial pneumonia, the leading cause of death in newborn infants. This crucial window was characterized by an abrupt influx of interleukin (IL)-22 producing group 3 innate lymphoid cells (IL22+ILC3) into the lungs of newborn mice. This influx was dependent on sensing of commensal bacteria by intestinal mucosal dendritic cells. Disruption of postnatal commensal colonization or selective depletion of dendritic cells interrupted the migratory program of lung IL-22+ILC3 and made the newborn mice more susceptible to pneumonia, which was reversed by transfer of commensal bacteria after birth. Thus, the resistance of newborn mice to pneumonia relied on commensal bacteria-directed ILC3-influx into the lungs, which mediated IL-22-dependent host resistance to pneumonia during this developmental window. These data establish that postnatal colonization by intestinal commensal bacteria is pivotal in the development of lung defenses in mice.

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.