Cutting Edge: Estrogen Drives Expansion of the CD4+CD25+ Regulatory T Cell Compartment

TLDR

CD4+CD25+ regulatory T cells are essential for immune tolerance, yet the factors that regulate their population and function remain largely unknown, despite evidence that estrogen protects against autoimmune disease. Our data show that estrogen (17‑β‑estradiol) increases FoxP3 expression and CD25+ cell numbers in vitro and in vivo, protects against experimental autoimmune encephalomyelitis, and that pregnancy‑induced estrogen similarly upregulates FoxP3, indicating estrogen promotes tolerance by expanding the regulatory T cell compartment.

Abstract

Abstract CD4+CD25+ regulatory T cells are crucial to the maintenance of tolerance in normal individuals. However, the factors regulating this cell population and its function are largely unknown. Estrogen has been shown to protect against the development of autoimmune disease, yet the mechanism is not known. We demonstrate that estrogen (17-β-estradiol, E2) is capable of augmenting FoxP3 expression in vitro and in vivo. Treatment of naive mice with E2 increased both CD25+ cell number and FoxP3 expression level. Further, the ability of E2 to protect against autoimmune disease (experimental autoimmune encephalomyelitis) correlated with its ability to up-regulate FoxP3, as both were reduced in estrogen receptor α-deficient animals. Finally, E2 treatment and pregnancy induced FoxP3 protein expression to a similar degree, suggesting that high estrogen levels during pregnancy may help to maintain fetal tolerance. In summary, our data suggest E2 promotes tolerance by expanding the regulatory T cell compartment.