Excess type I interferon disrupts developmental crosstalk and promotes premature distalization in trisomy 21 lungs

Abstract Pulmonary complications are a primary cause of morbidity and mortality in children with Down Syndrome resulting from Trisomy 21 (T21). We recently described congenital lung anomalies associated with T21, yet the underlying mechanisms remain elusive. Type I interferon (IFN-I) signaling is consistently hyperactivated in many T21 tissues. IFN-I is recognized as a key regulator of immune cell activation and differentiation, with an under-appreciated role in tissue development. In this study we examine the effects of over-activation and repression of IFN-I signaling in developing human lung tissues. Single-cell RNA sequencing indicates that IFN treatment of tissue explants largely recapitulates transcriptional changes associated with altered epithelial differentiation in T21 lungs. Lineage-specific cell co-culture experiments confirm that mesenchyme-driven IFN-I hyperactivation promotes epithelial bud remodeling, shifts progenitor cell identity, and suggests the induction of AT2-like programs. Our data show that IFN-I is necessary and sufficient to drive T21-related lung pathologies and provide a model system enabling therapeutic discovery.