ERb 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. 17{beta}-estradiol, a steroid sex hormone with established immunomodulatory roles, signals through the nuclear receptors ER and ER{beta}, which are expressed by CD4+ T cells. Expression of ER{beta} 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 ER{beta} in promoting the TGF{beta}-dependent differentiation of Foxp3+ Tregs, supporting the idea that ER{beta} has anti-inflammatory functions. In this study, we investigated the functional role of ER{beta} in effector T cells, which drive pathogenesis of many autoimmune diseases. We found that CD4+ T cells isolated from mice globally deficient in ER{beta} 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 ER{beta}-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 ER{beta} functions as a brake on T cell-mediated inflammation, thereby helping to maintain immune homeostasis. HighlightsO_LICD4+ T cells express the nuclear estrogen receptor ER{beta} C_LIO_LIER{beta}-deficient T cells express higher levels of inflammatory cytokines and are hyperproliferative ex vivo C_LIO_LIDeletion of ER{beta} increases T cell-mediated inflammation in a murine model of colitis C_LI CRediT authorship contribution statementSKM: 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.