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

ABSTRACT 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. Highlights CD4+ T cells express the nuclear estrogen receptor ERβ ERβ-deficient T cells express higher levels of inflammatory cytokines and are hyperproliferative ex vivo Deletion of ERβ increases T cell-mediated inflammation in a murine model of colitis CRediT authorship contribution statement SKM: investigation, formal analysis, visualization, writing – original draft; AVB: investigation, formal analysis, visualization, writing – original draft and review and editing; SMS: investigation and formal analysis; CMS: investigation and formal analysis, ADK: investigation, MLR: investigation, WBT: investigation; WAG: conceptualization, funding acquisition, project administration, resources, supervision, formal analysis, visualization, writing-review and editing.