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. In vitro , female hormones dose-dependently decreased IFN-γ production in T and NK cells but did not alter cytotoxic mediator production in these cells. 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.