Mothers living near high-traffic roads before or during pregnancy have increased odds of having children with asthma. Mechanisms are unknown. Using a mouse model, here we showed that maternal exposure to diesel exhaust particles (DEP) predisposed offspring to allergic airway disease/AAD (murine counterpart of human asthma) through programming of their NK cells; predisposition to AAD did not develop in ‘DEP’ pups that lacked NK cells and was induced in normal pups receiving NK cells from wild type ‘DEP’ pups. “DEP’ NK cells expressed GATA3 and co-secreted IL-13 and the ‘killer’ protease granzyme B in response to allergen challenge. Extracellular granzyme B did not kill but instead it stimulated protease-activated receptor 2 (PAR2) to cooperate with IL-13 in the induction of IL-25 in airway epithelial cells. Through loss-of-function and reconstitution experiments in pups, we showed that NK cells and granzyme B were required for IL-25 induction and activation of the type-2 immune response, and IL-25 mediated NK cell effects on type-2 response and AAD. Lastly, experiments using human cord blood and airway epithelial cells suggested that DEP might induce an identical pathway in humans. Collectively, we described an NK cell-dependent endotype of AAD that emerged in early life as a result of maternal exposure to DEP.
Qian Qian, Bidisha Paul Chowdhury, Zehua Sun, Jerica Lenberg, Rafeul Alam, Eric Vivier, Magdalena M. Gorska