Epithelial‐Associated CD207 + DCs Link Allergen Sensing and IL ‐25‐Driven Th2 Inflammation in Asthma

ABSTRACT Background IL‐25 is a key epithelial‐derived alarmin associated with T2‐high asthma, yet its downstream mechanisms remain poorly defined. CD207 (Langerin) + dendritic cells (DCs) are localized at the airway epithelial interface. However, whether these cells respond to epithelial‐derived cytokines and contribute to the Th2 immune response in asthma remains unclear. Methods Single‐cell RNA‐seq from healthy human lungs was analyzed to define the transcriptomic features of CD207 + DCs. Their function was validated in a house dust mite (HDM)‐induced asthma model using Cd207 −/− mice. Flow cytometry was performed on lung and mediastinal lymph nodes. DC–T cell co‐cultures were used to assess Th2 polarization. Epithelial–DC interactions were evaluated using transwell co‐culture with ALI‐differentiated tracheal epithelial cells. Clinical relevance was examined in airway samples from asthma patients in the U‐BIOPRED cohort. Results CD207 + DCs were enriched in intraepithelial compartments and exhibited increased MHC‐II and Claudin‐1 expression. In asthma, their abundance correlated with T2 signatures and Th2 markers (CRTH2, ST2). CD207 deletion reduced HDM uptake, Th2 cytokines, airway inflammation, and Th2 differentiation. IL‐25 induced CD207 + DCs and enhanced their Th2‐polarizing capacity in vitro. An IL‐25–CD207 co‐expression score correlated with IL‐4/IL‐5/IL‐13 levels and was higher in steroid‐naïve patients with severe asthma. Conclusion Our study identifies CD207 + DCs as epithelial‐associated antigen‐presenting cells that bridge IL‐25 signaling and Th2 polarization in allergic asthma. Targeting the IL‐25–CD207 axis may offer therapeutic opportunities for T2‐high asthma.