5 - LOSS OF ESTROGEN RECEPTOR BETA IN A SPONTANEOUS MODEL OF CROHN'S-LIKE ILEITIS REVEALS SEX-SPECIFIC FUNCTIONS OF ESTROGEN SIGNALING AMONG INTESTINAL REGULATORY T CELLS
(Room Pinyon 3)
18 Jan 18
2:25 PM
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2:40 PM
Tracks:
Clinical and Research Challenges, Lloyd Mayer, MD, Young IBD Investigators Workshop
Introduction Regulatory T cells (Tregs) isolated from IBD patients function properly ex vivo, but are unable to restrain chronic inflammation in situ. The goal of this project is to investigate the mechanism(s) by which 17-beta estradiol (estrogen, E2) contributes to Treg dysfunction in an experimental model of Crohn’s-like ileitis. Background Females are more likely to develop Crohn’s disease (CD) than males, suggesting a potential role for E2 signaling. Interestingly, E2 has been shown to be immunoprotective under homeostatic conditions by inducing the peripheral differentiation of Tregs. Using a spontaneous model of CD-like ileitis which recapitulates the CD female sex bias, we investigated the role of E2 signaling to estrogen receptor beta (ERb) in control of Treg differentiation and function. Aims (1) To study the effects of ERb loss-of-function on SAMP ileitis and intestinal Treg frequency and function; (2) To determine whether E2/ERb signaling contributes to sex differences in SAMP ileitis. Methods We generated SAMP/YitFc mice (SAMP) harboring a global deletion of ERb (SAMP-ERb-KO). Mice were assessed for ileitis at 6, 12, and 20 weeks of age by a pathologist blinded to mouse genotype and gender. Tregs isolated from the mesenteric lymph node (MLN) or ileum were assessed by flow cytometry and/or qPCR for phenotypic and functional markers including Foxp3, Helios, CD39, CD73, LAP, and IL-17. Results SAMP-ERb-KO female (-F) mice displayed significantly worse ileitis than SAMP-ERb-KO-M. Overall frequencies of Tregs (CD4+CD25+Foxp3+) were consistent among SAMP-ERb-KO-M and –F mice and SAMP-ERb+/+ controls, although SAMP-ERb-KO-F mice exhibited a significant reduction in CD39+CD73+ Tregs compared to all other groups. RNAseq analysis of MLN-derived Tregs revealed novel gene expression profiles among SAMP-ERb-KO-F Tregs. Conclusion ERb loss-of-function studies reveal important, novel roles for E2/ERb signaling in the maintenance of ileal Tregs from female SAMP mice.