Sexual Dimorphism in Skin Immunity is Mediated by an Androgen-ILC2-Dendritic Cell Axis

Differences in biologic sex have been associated with differences in immunity, with females having stronger innate and adaptive immune responses. However, specific hormonal factors have not been well studied. The purpose of the study was to investigate and understand the factors that contribute to sexual dimorphism in immune responses within barrier tissues.This study examines the differences in innate and adaptive immune responses in barrier tissues between females and males using mouse models. As such, no human subjects were involved.The study used various strains of mice, including C57BL/6NTac, Red5, Rag1−/−, Rag2−/−γc−/−, Csf2flox–tdTomato and Vav1iCreCsf2flox–tdTomato, Csf2ra−/−, OT-I OVA-specific CD8 + TCR transgenic, Csf2−/−, Il7rcreArfl/fl (female), Il7rcreArfl/Y (male), and wildling (C57BL/6 mice reconstituted with wild mouse-derived microbiota and pathogens) mice. Experiments involved topical application of bacteria and fungi and intradermal injections of S.aureus to assess immune responses. Tissues were processed using specific protocols for cell isolation, and various assays, such as in vitro restimulation, flow cytometry, in vivo treatments, and genetic manipulations, were performed to analyze immune cell function and gene expression patterns.In the skin and lungs, female mice exhibited higher levels of various T cell subsets, including Th17, Th1, and Tregs, compared with males. No differences were found in the gut at baseline. In the skin, but not the lung or gut, germ-free mice females exhibited higher T cell counts. Upon exposure to microbes, female skin demonstrated enhanced barrier protection and more robust T cell responses. Interestingly, ovary removal did not affect female skin T cell populations, but castration in males normalized IL-17A-producing cells and Tregs to female levels, reducing the bacterial burden and allowing males to develop similar T cell responses as females. Female skin had a denser network of resident dendritic cell (DC) subsets with higher activation gene expression. Testosterone negatively regulated DC homeostasis, and when androgen signaling was disrupted, innate lymphoid cells type 2 (ILC2s) increased in male skin. A higher absolute number of granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing ILC2s were found in the skin of females compared with males. Furthermore, injecting ILC2s or ILC2-derived GM-CSF into immune-deficient mice restored DC networks, particularly in females. The results indicate that androgens negatively regulate ILC2s, leading to decreased accumulation and activation of DCs in the skin, which results in lower local immunity in males compared with females.This study highlights the effect of sex on immune responses in different barrier tissues. Although immune differences were not seen in the gut, lung experiments showed that microbiota was necessary to induce the sex bias. In contrast, in the skin, female mice exhibit enhanced adaptive immune responses, including increased T cell subsets, including Th17 and Treg cells, stronger DC networks, and increased cytokine production compared with males. These differences are partly attributed to androgen signaling negatively affecting the density and function of ILC2 cells, which produce GM-CSF critical for DC homeostasis. Male castration or androgen receptor deficiency in lymphoid cells normalizes immune parameters and improves microbial response, suggesting a direct role of male sex hormones in dampening immune responses.This study is important for pediatricians as it enhances understanding of how sex-based differences in immune function can affect children’s health, particularly regarding skin immunity and susceptibility to allergies, infections, autoimmune disorders, and cancers. The findings reveal that female mice have more robust skin immune responses because of higher T cells and DCs, which may be mirrored in humans. Additionally, the study highlights the significant role of the microbiome in shaping immune responses in different tissues, suggesting that treatments targeting microbiota may be beneficial. Understanding the impact of hormones, such as testosterone, on immune function is particularly relevant for managing conditions during puberty or other transitions. Ultimately, the findings underline the importance of considering sex as a fundamental health factor, potentially leading to more personalized and effective treatments for children.