Signaling of 17β-estradiol (estrogen) through its two nuclear receptors, α and β (ERα, ERβ), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERβ-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERβ-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn’s disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERβ-specific signaling in TGF-β–dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERβ, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERβ was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERβ normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.

17β-雌二醇（雌激素）通过其两个核受体α和β（ERα，ERβ）发出信号是转录调节的重要机制。尽管内质网由免疫系统细胞广泛表达，但它们调控免疫应答的机制仍知之甚少。慢性炎症性疾病（包括系统性红斑狼疮和炎症性肠病）患者的ERβ特异性信号传导减少，我们以前的工作表明ERβ特异性信号传导失调有助于雌性SAMP / YitFC小鼠（一种自发模型的肠道炎症）的增强。克罗恩病样回肠炎。本研究建立在这些先前的观察的基础上，以鉴定ERβ特异性信号传导在TGF-β依赖性调节性T细胞（Treg）分化中的非冗余免疫保护作用。使用工程改造为缺乏ERβ整体表达的同类SAMP小鼠品系，我们观察到女性肠道炎症的特异性加剧，并伴随着肠道Treg频率和功能的显着降低。在缺乏ERβ的情况下Treg抑制功能受损与异常表达有关Tsc22d3（GILZ）是一种在成熟Tregs中通常不表达的糖皮质激素应答转录因子，离体数据显示，在成熟Tregs中强迫GILZ的过表达会抑制其抑制功能。总的来说，我们的发现确定了肠中雌激素介导的免疫调节的途径，由此ERβ的稳态表达通常起到限制GILZ的Treg特异性表达的作用，从而维持有效的免疫抑制作用。我们的数据表明，糖皮质激素和类固醇性激素信号传导之间的转录串扰代表了慢性炎性疾病中一个重要且未被充分研究的调节节点。