IL-33/TGF-β/IL-4-induced bone marrow-derived DC9 subset promotes Th9 differentiation and allergic airway inflammation

Summary Dendritic cells (DCs) are professional antigen-presenting cells that exhibit significant heterogeneity in development and function. This study found that among 17 cytokines screened, only IL-33 could induce DCs to display a Th9-type cytokine profile, including IL-9, IL-4, and IL-13, in vitro. The response of DCs to IL-33 was synergistically enhanced by TGF-β and IL-4, defining a distinct subset termed DC9. Transcriptomic analysis revealed that DC9 possesses a unique gene expression signature, particularly in cytokine/chemokine clusters, compared to conventional DCs. Mechanistically, DC9 polarization depends on the JAK-STAT6-IRF4 signaling pathway. Functionally, DC9 preferentially drives naive CD4⁺ T cell differentiation toward Th9 cells in vitro. In an ovalbumin-induced allergic airway inflammatory mouse model, DC9 cells were detectable in lungs and adoptive transfer of DC9 exacerbated disease severity, and increased pulmonary Th9 cells. Collectively, we identify DC9 as a novel DC subset induced by IL-33/TGF-β/IL-4 through the JAK-STAT6-IRF4 axis, which promotes Th9 differentiation and aggravates allergic airway inflammation.