Androgen signaling shapes the sexual differences of skin immunity by regulating ILC2 and dendritic cells

Abstract The skin immune system mediates the skin health status, but the sex differences of the skin immune system are still unclear. This study aims to investigate sex differences in the skin immune system and decipher the underlying regulatory factors. We found that female mice have a higher magnitude of adaptive immune responses during commensal bacteria association and pathogen infection. Correspondingly, females have a higher level of skin dendritic cells (DCs), which play a fundamental role in commensal-induced adaptive immune responses. These sex differences were regulated by male sex hormones, that castration of males normalized the sex differences in the level of skin immune cells as well as the adaptive immune responses to bacteria. However, our scRNA-seq data reveals that androgen receptor is not expressed in DCs, but highly expressed in skin ILC2. Females have a significantly higher level of ILC2 than males and ILC2 from females also have a more activating gene expression signature than ILC2 from males. Females also have a significantly higher level of ILC2-produced IL-13 and GM-CSF than male mice. In addition, our data reveal that IL-13 and GM-CSF play a critical role to maintain the level of skin DCs, that IL-13/GM-CSF deficient mice have a remarkable decrease of skin DCs, and the sex differences of DCs are also largely impaired. Therefore, based on these findings, we suggest that androgen signaling negatively regulates the level of skin ILC2 and DCs, thereby shaping sex-specific skin immunity to commensals, pathogens, and/or other stimuli. Collectively our work proposes a mechanism for the heighten immunity observed in female and have important implication for our understanding of tissue immunity in the context of infection and cancer.