Tissue niches for ILC3 development in newborn's lung

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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.