ILC2s govern sex-differential immunity in skin

The mechanisms driving sex differences in immunity are poorly understood and likely vary by body site; thus Chi et al. investigated the mechanistic basis of sex differences in tissuespecific immunity in a recent paper in Science.They focused on the complex network of immune cells in murine skin to demonstrate that an androgen-ILC2-dendritic cell axis drives sex differences in immune homeostasis in the skin that is modulated by sex-differential microbiota.Sex differences in innate and adaptive immunity, susceptibility to multiple diseases and responses to therapeutic interventions are widely described, 1 yet the mechanisms remain mostly elusive.The two dominant factors thought to drive immunological sex differences are sex hormones and sex-linked immune response genes, mostly X-chromosome linked. 1 The microbiome also differs in males and females due to bi-directional interactions between the immune system, sex hormones and microbial communities, leading to the concept of the microgenderome, 2 which further contributes to sex-differential immunity.Chi et al. 3 investigated the mechanisms of sex differences in tissue-specific immunity in mice and identified the skin as a key organ exhibiting marked sex differences in immune cell composition, with females having greater numbers of type 1 (Th1, Tc1), type 17 (Th17, Tc17) and regulatory T cell (Treg) subsets.Differences were apparent in germ-free mice confirming that they were not driven by sex-differential microbiota, while introducing microbiota-augmented type 17 and Treg responses in females.The authors went on to demonstrate that females have more robust immunity to skin commensals and invading bacterial pathogens than males.Females had greater Tc1 and IL-17A expressing T cell subsets in response to colonization with Staphylococcus epidermidis, Corynebacterium accolens and Candida albicans which in turn led to enhanced immune responses in keratinocytes and lower bacterial load among females.The immune response to skin infection with Staphylococcus aureus similarly resulted in greater Th1 and Th17 immunity in females compared to males.Pre-pubertal male castration led to a loss of the above sex differences, whereas ovariectomy had no effect, suggesting that male sex hormones drive the lymphoid sex differences and response to microbiota.Within the skin dendritic cell (DC) network, females had greater DC numbers which expressed more co-stimulatory and survival genes and had greater migratory and antigen presenting capacity, whereas male DCs expressed more negative regulatory genes.Castration and hormone treatment experiments demonstrated that male sex hormones negatively regulate skin DC homeostasis and function.Since skin DCs do not express the androgen