Complement-producing adventitial fibroblasts form an IL-33 alarmin hub that maintains ILC2s during airway allergy

Once considered mere scaffolds, mesenchymal stromal cells are now recognized as actively shaping airway immunity. We identify adventitial fibroblasts (AFs) in perivascular/peribronchial cuffs as a dominant source of complement C3. At baseline, a discrete subset of AF co-expresses C3 and IL-33. Upon allergen exposure, these C3⁺IL-33⁺ AFs expand and increase their production of both C3 and IL-33, indicating a shift toward an allergic AF phenotype. Disruption of C3 production in AFs abrogates IL-33 expression, underscoring the essential role C3 plays in maintaining an allergic AF phenotype. Functionally, C3 from AFs is required to drive allergen-induced group 2 innate lymphoid cell (ILC2) responses. C3⁺ AFs not only support ILC2s but are also influenced by ILC2-derived IL-13, which, in turn, promotes AF function, perpetuating the allergic response. These findings reveal that aberrant C3 production by the adventitial stroma orchestrates a pathogenic AF-ILC2 niche that promotes allergic inflammation.