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

Pulmonary immunity is essential for maintaining lung function by protecting against infection and injury ^1,2 . As the distal respiratory airways (also termed terminal and respiratory bronchioles) are structures unique to humans and other large mammals, the cellular mediators of immunoregulation in this region remain elusive. Here, using human pluripotent stem cell-derived lung organoids and clinical specimens, we reveal previously unrecognized innate immune defense in human distal airways mediated by respiratory airway secretory (RAS) cells. Lineage tracing identified RAS cells as descendants of SOX9 ^bright NKX2-1 ^bright progenitors. Single-cell transcriptomics elucidated that RAS cells exhibited a distinct immune-competent phenotype, characterized by enrichment of genes associated with viral host entry and pattern recognition receptor signaling. Functionally, RAS cells exhibited enhanced antiviral activity against respiratory syncytial virus by upregulating interferon-stimulated genes. Furthermore, upon stimulation with bacterial flagellin or Pseudomonas aeruginosa (PAO1), RAS cells initiated robust immune responses through TLR5 activation, resulting in CXCL8 release to recruit and activate neutrophils ³ , which was markedly suppressed by a selective TLR5 inhibitor. Notably, RAS cells from chronic obstructive pulmonary disease patients with PAO1 infection showed significant secretion of chemokines, including CXCL8 and CXCL10, directly linking these cells to disease-associated inflammation. Collectively, our findings establish RAS cells as critical immune sentinels in the human distal respiratory airways, filling a gap in understanding human distal lung immunity and its role in maintaining lung function and chronic lung diseases.