Early life exposure to house dust mite allergen prevents experimental allergic asthma requiring mitochondrial H 2 O 2

Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H 2 O 2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H 2 O 2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia, and increased airway hyperreactivity. WT-Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naive mice. In contrast, the lungs of MCAT-Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H 2 O 2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.