Maternal diesel particle exposure promotes offspring asthma through NK cell–derived granzyme B
Qian Qian, … , Eric Vivier, Magdalena M. Gorska
Qian Qian, … , Eric Vivier, Magdalena M. Gorska
Published May 14, 2020
Citation Information: J Clin Invest. 2020;130(8):4133-4151. https://doi.org/10.1172/JCI130324.
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Research Article Immunology Pulmonology

Maternal diesel particle exposure promotes offspring asthma through NK cell–derived granzyme B

Abstract

Mothers living near high-traffic roads before or during pregnancy are more likely to have 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 WT DEP pups. DEP NK cells expressed GATA3 and cosecreted IL-13 and the killer protease granzyme B in response to allergen challenge. Extracellular granzyme B did not kill, but instead 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 that IL-25 mediated NK cell effects on type 2 response and AAD. Finally, experiments using human cord blood and airway epithelial cells suggested that DEP might induce an identical pathway in humans. Collectively, we describe an NK cell–dependent endotype of AAD that emerged in early life as a result of maternal exposure to DEP.

Authors

Qian Qian, Bidisha Paul Chowdhury, Zehua Sun, Jerica Lenberg, Rafeul Alam, Eric Vivier, Magdalena M. Gorska

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Figure 2

DEP NK cells have increased capacity to produce type 2 cytokines and degranulate.

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DEP NK cells have increased capacity to produce type 2 cytokines and deg...
(A–G) Frequencies and features of lung NK cells in PBS-PBS, DEP-PBS, PBS-OVA, and DEP-OVA pups. (A) Percentages of NK cells (CD3–CD19–NK1.1+) in live lung cells. n = 9–10 mice per group. (B) Flow cytometry plots to detect NK cell subsets. CD3–CD19–NK1.1+ live lung cells were analyzed for CD11b and CD27. (C and D) Percentages of indicated subsets in live lung NK cells. n = 9–10 mice per group (B–D: gating strategy in Supplemental Figure 2A). (E) Left: flow cytometry plots to measure degranulated (CD107a+) NK cells in lung digests. Lung cells were incubated at 37°C with PE-labeled anti-CD107a or isotype control IgG, monensin, brefeldin A, IL-2, and IL-15, and then stained with eFluor506 and antibodies for surface markers. Live NK cells (eFluor506–CD3–CD19–NK1.1+) were analyzed for NK1.1 versus CD107a. Right: percentages of CD107a+ NK cells in live lung NK cells. n = 8. (F) Percentages of IL-5+ and IL-13+ NK cells in live lung NK cells. Result was obtained after ex vivo stimulation with PMA/ionomycin. n = 6. (G) Left: flow cytometry plot to identify GATA3+ NK cells. CD3–CD19–CD127–NK1.1+ live lung cells (no ex vivo stimulation) from PBS-PBS and DEP-PBS pups were analyzed for GATA3 or binding of an isotype control immunoglobulin. Right: percentages of GATA3+ NK cells in live lung NK cells. n = 5. Data are representative of 2 independent experiments and are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA with Tukey’s post hoc test (A and C–F); 2-tailed unpaired t test (G).