Abstract
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
) maintaining lung tolerance at steady state but promotes T
2 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
2-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
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.
