Developmental origin of sex-specific differences in lung-resident immunity

Sex differences in prevalence, morbidity and mortality of lung diseases, are well established. The role of lung-resident immunity in the reported sexual dimorphism and its origin during fetal lung and immune development remains elusive. Here, we hypothesized that prenatal stress programs sex-specific differences in lung-resident immune cells, hereby contributing to the sexual dimorphism in respiratory diseases. Pregnant C57BL/6 mice were exposed to sound stress on gestational days 9.5, 11.5, 13.5, and 15.5. The lungs of their adult offspring and non-stressed controls were collected and lung-resident immunity was characterized using flow cytometry. Male control offspring exhibited higher frequencies of alveolar macrophages (AM) compared to control females, which was reversed upon prenatal stress exposure, with prenatally stressed females having more AM than males. Prenatal stress facilitated also a sex difference in CD11b+ dendritic cells, with females having more than males. Additionally, naïve female lungs contained more γδ T cells than male lungs, but after prenatal stress, this population decreased in females. Prenatal stress affects lung-resident immunity in a sex-specific manner and may thus contribute to the sex-specific manifestation of respiratory immune diseases.