In vivo reprogramming of pathogenic lung TNFR2⁺ cDC2s by IFNβ inhibits HDM-induced asthma

Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2⁺ conventional DC2 subset (cDC2s) that induces regulatory T cells (T_regs) maintaining lung tolerance at steady state but promotes T_H2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2⁺ cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed T_H2-promoting pathogenic TNFR2⁺ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2⁺ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung T_reg induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2⁺ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy.