Sex hormones regulate the sexual dimorphism of the lung resident immune milieu

Abstract

A strong sex-bias characterizes many respiratory immune diseases and has been attributed to sexually dimorphic immune responses. However, the role of lung-resident immunity in this context remains elusive. Here, we thoroughly characterized the lung-resident immune landscape in male and female mice, with a special focus on sex hormone effects in this context. Androgens were found to exert the strongest effects, markedly impacting B cells and neutrophils in both male and female lungs. Castrated males exhibited increased, while testosterone-treated females and males decreased lung-residing B cells. Testosterone supplementation of castrated males and females resulted in increased lung-residing neutrophils. Sex-mismatched orthotopic lung transplantation further supported these findings, since lungs isolated from female donors exhibited reduced tissue-residing B cells after their transplantation into male recipients. For the remaining lung-resident immune cell populations, sex differences were observed at the level of cell frequencies, with male lungs exhibiting higher frequencies of alveolar macrophages and lower frequencies of lung-resident dendritic cells and CD4⁺ tissue-resident memory T cells. Castration reversed some of these findings. Our findings highlight that the sexual dimorphism of the lung-resident immune landscape is modulated by sex hormones and especially androgens, thereby providing insights into the sex-specific manifestation of respiratory immune diseases.