Respiratory Airway Secretory Cells act as Immune Sentinels in Human Distal Airways

Pulmonary immunity in the human distal respiratory airways is essential for lung function but remains less explored. Here we report that respiratory airway secretory (RAS) cells, a newly identified lung epithelial population unique to humans and large mammals, act as immune sentinels in the distal airways by safeguarding against infection and injury. Leveraging human pluripotent stem cell-derived lung organoids, animal models, and clinical specimens, we elucidate that RAS cells arise from distal lung progenitors and exhibit context-dependent immune competence. Upon viral or bacterial challenge, RAS cells display interferon-mediated or TLR5-dependent defense responses, respectively. In chronic obstructive pulmonary disease, they produce elevated adaptive immune responses. Notably, complement C3 is upregulated under these conditions and is suppressed by a selective TLR5 inhibitor. Our findings reveal RAS cells as previously unrecognized sensors and effectors of mucosal immunity at human distal airways, highlighting the TLR5–complement axis as a potential therapeutic target in lung disease.