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

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.

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.

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.

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.