In Vivo Reprogramming Of Pathogenic Lung Tnfr2+ Cdc2s By Ifn Beta 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(H)2 response during house dust mite (HDM)-induced asthma. Lung IFN beta is essential for TNFR2+ cDC2s-mediated lung tolerance. Here, we showed that exogenous IFN. reprogrammed T(H)2-promoting pathogenic TNFR2+ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFN beta, not IFN beta, activated ERK2 signaling in pathogenic lung TNFR2+ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung Treg induction. Last, human IFN beta reprogrammed pathogenic human lung TNFR2+ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFN beta-specific ERK2-FAO pathway that might be harnessed for DC therapy.