Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn’s-like ileitis

The incidence and severity of Crohn’s disease (CD) are increased in female patients. Using SAMP1/YitFc (SAMP) mice, a spontaneous model of chronic intestinal inflammation that displays histologic and pathogenic similarities to human CD, we investigated the potential mechanism(s) contributing to sex differences observed in CD. Similar to gender differences observed in CD patients, SAMP female (SAMP-F) mice displayed an earlier onset and more severe ileitis compared to SAMP males (SAMP-M). Further, T regulatory cells (Tregs) from gut-associated lymphoid tissue (GALT) of SAMP-F were reduced in frequency and impaired in their in vitro and in vivo suppressive functions compared to SAMP-M Tregs. Given the interaction between sex hormones and Treg function, we investigated the possible role of estrogen (E2) in SAMP ileitis. SAMP-M responded to exogenous E2 administration by expanding Treg frequency and reducing ileal inflammation, whereas SAMP-F were resistant. Conventional T cells (Tconv) and Tregs responded differentially to estrogen signaling, leading to distinct immunoprotective effects mediated by distinct estrogen receptor (ER) isoforms. These mechanisms were impaired in T cells from SAMP-F mice. Thus, hormone signaling influences the expansion and function of GALT Tregs in an ER-dependent manner and contributes to gender-based differences in experimental CD.