ERβ 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, a steroid sex hormone with established immunomodulatory roles, signals through the nuclear receptors ERα and ERβ, which are expressed by CD4⁺ T cells. Expression of ERβ is reduced in CD4⁺ T cells isolated from autoimmune disease patients, suggesting that dysregulated E2 signaling contributes to inflammation. We previously identified a novel role for ERβ in promoting the TGFβ-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. We found that CD4+ T cells isolated from mice globally deficient in ERβ exhibit enhanced proliferation and Th1 polarization ex vivo, together with elevated levels of proinflammatory cytokines in response to T cell receptor (TCR) stimulation. We also found that transfer of ERβ-KO T cells to immunodeficient mice results in significantly worse inflammation in a murine model of colitis. Together, these findings suggest that T cell-specific ERβ functions as a brake on T cell-mediated inflammation, thereby helping to maintain immune homeostasis.