Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment.
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-beta-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 alpha-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.
Department of Neurology, Oregon Health and Science University, and Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA.
Magdalena J
MJ
Polanczyk
Bryan D
BD
Carson
Sandhya
S
Subramanian
Michael
M
Afentoulis
Arthur A
AA
Vandenbark
Steven F
SF
Ziegler
Halina
H
Offner
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000172:deficiency; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011960:Receptors, Estrogen; D015375:Receptors, Interleukin-2