Lee, James

Abstract Type 2 immune cells and eosinophils are transiently present in lung tissue not only in pathology but also during normal postnatal development. However, the lung developmental processes underlying postnatal airway recruitment of eosinophils after birth remain unexplored. We determined that in mice, mature eosinophils are recruited to the lung during P3–14, which corresponds to the primary septation/alveolarization phase of lung development. Developmental eosinophils peaked during P10–14 and exhibited Siglec-Fmed/highCD11c−/low phenotypes, similar to allergic asthma models. By interrogating the lung transcriptome and proteome during peak eosinophil recruitment in postnatal development, we identified markers that functionally capture mesenchymal-epithelial interface establishment (Nes, Smo, Wnt5a, Nog) and provisional extracellular matrix (ECM) deposition (Tnc, Postn, Spon2, Thbs2) as key lung morphogenetic events associating with eosinophils. We identifiedTenascin-C (TNC) as one of the key ECM markers in the lung epithelial-mesenchymal interface at the RNA and protein levels, consistently associating with eosinophils in development and disease. By RNA-seq analysis, naïve murine eosinophils cultured with TNC-enriched ECM significantly induced expression of Siglec-F, CD11c, eosinophil peroxidase, and other markers typical for activated eosinophils in development and allergic inflammatory responses. TNC knockout mice had an altered eosinophil recruitment profile in development. Collectively, our results indicate that lung morphogenetic processes associated with heightened Type 2 immunity are not merely tissue “background” but specifically guide immune cells both in development and pathology.