Environmentally driven immune imprinting protects against allergy

, the biological mechanisms that underpin environmentally mediated protection from allergy are unknown. Here we show, using a mouse model of allergic disease, that exposure to immunostimulatory environments generated cross-reactive adaptive immune memory, which tracked with obstructed type II immune responses upon allergen exposure. We found that engagement of cross-reactive adaptive immunity protected against future allergic sensitization and suppressed established allergic responses. Cross-reactivity in a tolerogenic context also prevented allergy, with the effect extending across antigenically complex exposures even at low protein sequence similarity. Our findings demonstrate a mechanistic relationship between environment and allergy, with general implications for adaptive immune function in natural settings.