ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity

The development of therapies for multiple sclerosis targeting pathogenic T cell responses remains imperative. Previous studies have shown that estrogen receptor (ER) beta ligands could inhibit experimental autoimmune encephalomyelitis. However, the effects of ER beta-specific ligands on human or murine pathogenic immune cells, such as Th17, were not investigated. In this article, we show that the synthetic ER beta-specific ligand 4-(2-phenyl-5,7-bis[trifluoromethyl] pyrazolo[1,5-a] pyrimidin-3-yl) phenol (PHTPP) reversed established paralysis and CNS inflammation, characterized by a dramatic suppression of pathogenic Th responses as well as induction of IL-10-producing regulatory CD4(+) T cell subsets in vivo. Moreover, administration of PHTPP in symptomatic mice induced regulatory CD4(+) T cells that were suppressive in vivo. PHTPP-mediated experimental autoimmune encephalomyelitis amelioration was canceled in mice with ER beta-deficient CD4(+) T cells only, indicating that expression of ER beta by these cells is crucial for the observed therapeutic effect. Importantly, synthetic ER beta-specific ligands acting directly on CD4(+) T cells suppressed human and mouse Th17 cells, downregulating Th17 cell signature gene expression and expanding IL-10-producing T cells among them. TGF-beta 1 and aryl hydrocarbon receptor activation enhanced the ER beta ligand-mediated expansion of IL-10-producing T cells among Th17 cells. In addition, these ER beta-specific ligands promoted the induction and maintenance of Foxp3(+) T regulatory cells, as well as their in vitro suppressive function. Thus, ER beta-specific ligands targeting pathogenic Th17 cells and inducing functional regulatory cells represent a promising subset of therapeutic agents for multiple sclerosis.