Estrogen receptor beta limits T cell-mediated inflammation to maintain immune homeostasis.

Many autoimmune diseases exhibit a female sex bias in prevalence and severity, yet the mechanisms for this remain unclear. 17β-estradiol (E2) is a steroid sex hormone with established immunomodulatory roles in CD4+ T cells, which express the nuclear estrogen receptors ERα and ERβ. Autoimmune disease patients exhibit reductions in ERβ expression, suggesting that dysregulated E2 signaling contributes to inflammation. We previously identified a novel role for ERβ in promoting the TGF-β-dependent differentiation of Foxp3+ Tregs, supporting the idea that ERβ has anti-inflammatory functions. In this study, we investigated the functional role of ERβ in effector T cells, which drive pathogenesis of many autoimmune diseases. CD4+ T cells isolated from mice globally deficient in ERβ (ERβ-KO) showed enhanced proliferation and polarization to Th1 and Th17 populations ex vivo and conferred more severe inflammation and experimental colitis when transferred to immunodeficient Rag-KO mice. Treatment of ERβ-KO T cells ex vivo with anti-CD3/28 and PMA/ionomycin resulted in robust activation-induced production of Th17-associated cytokines, suggesting that ERβ normally functions to restrain Th17. Collectively, our data support a model in which reduced ERβ expression may contribute to loss of immunoregulatory signaling and enhanced T cell-driven inflammation.