Murine CD4+T cells exhibit sexually dimorphic responses to estrogen signaling

Abstract Many autoimmune diseases exhibit sexual dimorphism. 17β-estradiol (estrogen, “E2”), a steroid sex hormone primarily known for its reproductive roles, has also been shown to modulate CD4+ T cells. E2 signals through two nuclear receptors, ERα and ERβ, which regulate gene transcription through direct DNA binding and other mechanisms. We previously showed that in the SAMP/YitFC model of Crohn’s-like ileitis, loss of ERβ enhanced inflammation selectively in female mice. We also found that loss of ERβ resulted in decreased expression of Foxp3 in CD4+ T cells, suggesting that ERβ is required for differentiation of Foxp3+ Tregs. These prior findings suggest a pro-inflammatory role for ERα and anti-inflammatory role for ERβ, potentially in a sex-specific manner. In the current study, we investigated mechanisms of E2 signaling in CD4+ T cells isolated from males vs. females. Using standard in vitro assays, we found that the proliferation of TGFβ-induced regulatory T cells (Tregs) was enhanced in female cells co-treated with E2 compared to male cells, suggesting that E2 enhances Treg differentiation more strongly in females. Interestingly, using the CD45RB T cell transfer model of colitis, we found that recipients of female donor cells exhibited more severe disease compared to recipients of male cells, suggesting that female-derived CD45RB highT cells are more colitogenic than male cells. Future studies will determine the effect of E2 signaling on both effector and regulatory CD4+ T cell populations, identifying the contributions of ERα vs. ERβ-specific signaling in these T cell subsets and the functional impact of these signaling pathways in males versus females. Supported by grants from NIH (R01DK128143, R03DK123579, T32AI089474)