Nuclear estrogen receptors modulate regulatory T cell suppressive function 2309981

Abstract Introduction Autoimmune diseases are driven by an intricate combination of genetic and epigenetic factors, but the specific mechanisms underlying the etiologies of these disorders are not fully understood. 17β-estradiol (estrogen, E2) is a steroid sex hormone with potent immunoregulatory functions that contributes to various autoimmune diseases. E2 signaling through the nuclear estrogen receptors alpha and beta (ERα and ERβ) have clear immunomodulatory effects, with ER+ generally promoting and ERβ generally restraining inflammation. Previous work from our lab demonstrated that ERβ-specific signaling is reduced in inflamed mucosal tissues and T cells isolated from female Crohn’s disease patients, similar to previous reports in lupus patients, supporting the premise that ERβ functions to negatively regulate inflammation. Methods Our current study investigates the functional roles of ERβ in regulatory T cells (Tregs), in which we hypothesized that ERβ promotes Treg suppressive function. To test this, we performed ex vivo Treg suppression assays by co-culturing WT effector T cells (Teffs) with WT, ERα-KO, or ERβ-KO Tregs with or without E2. We also tested Treg suppression in vivo using a T cell transfer of colitis model. Immunodeficient Rag2-KO mice were co-injected with WT Teffs (CD4+CD25-) and WT, ERα-KO, or ERβ-KO Tregs (CD4+CD25+) to test the ability of Tregs to prevent colitis development. Results Our results show that E2 treatment reduces ex vivo suppressive ability of WT and ERβ-KO Tregs, as proliferation of Teffs is enhanced in these groups. In line with this, ERβ-KO Tregs are less suppressive in vivo. Rag2-KO recipients of ERβ-KO Tregs display more severe disease compared to recipients of WT Tregs, including stunted weight gain and increased histological inflammation. Conclusion These findings show that deletion of ERβ results in impaired Treg suppression, thus supporting a critical role for ERβ in promoting Treg function both ex vivo and in vivo. Funding Source NIH/NIDDK Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)