Impaired estrogen signaling underlies regulatory T cell loss-of-function in the chronically inflamed intestine

Significance

This study identifies a mechanism by which 17β estradiol (estrogen) contributes to peripheral tolerance via modulation of regulatory T cell (Treg) differentiation and function. Our results show that estrogen signaling through the nuclear receptor ERβ is required for TGF-β–dependent differentiation of Tregs, a critical pathway for peripheral Treg differentiation in the gut. Female patients with Crohn’s disease express significantly lower levels of ERβ in peripheral T cells and the intestinal mucosae. Tregs deficient in ERβ express aberrant levels of Tsc22d3 (GILZ), a protein not normally expressed in Tregs and that interferes with functional Treg suppression. Our findings support a pathway by which ERβ-specific signaling normally functions to limit GILZ expression in Tregs, thus maintaining peripheral tolerance in the gut.

Abstract

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.