Female hormones enhance skin T cell expansion and suppress IFN-γ production.

Introduction: Estrogen receptors (ERs) regulate immune function, but their expression across immune cell subsets and hormone responsiveness in human skin are not fully understood. Methods: We used 10-color flow cytometry to quantify ER (ERα, ERβ, and GPER1) expression in peripheral blood mononuclear cells (PBMCs) from healthy donors. We analyzed sex hormone gene expression using public single-cell RNA datasets. Skin immune responses to sodium lauryl sulfate (SLS) were assessed in pre- and post-menopausal women, with or without hormone replacement therapy (HRT). Furthermore, we measured the production of mediators in the ER expressing immune cytotoxic cells, specifically T and NK cells, in response to pre- and post-menopausal hormone cocktails. Results: ERα was predominantly expressed on the membrane of NK and NKT cells, while ERβ was mainly intracellular and showed low expression across subsets. GPER1 displayed a similar membrane distribution to ERα but at lower expression levels. T cells displayed moderate membrane ERα and lower GPER1 expression. Gene expression analysis in women revealed strong ESR1 and ESR2 expression in T cells. In inflamed skin, HRT selectively increased T cell numbers after SLS exposure in post-menopausal women. Conclusions: ER expression levels and localization vary by immune cell subset, indicating that estrogen modulates immune responses in a cell-specific manner. Sex hormones differentially impact T and NK cell populations during skin inflammation, by increasing T cell numbers and, reducing IFN-γ, without altering cytotoxic activity. These findings demonstrate that female sex hormones significantly influence immune responses in inflamed and aging skin and may guide the development of targeted therapeutic strategies.