Estrogen receptor alpha (ER alpha) deficiency in macrophages results in increased stimulation of CD4(+) T cells while 17 beta-estradiol acts through ER alpha to increase IL-4 and GATA-3 expression in CD4(+) T cells independent of antigen presentation

The effects of 17 beta-estradiol (E-2) on immune function have been extensively reported. The effects are dependent on concentration and duration of exposure and potential differences in signaling between the known E-2 receptors, estrogen receptors (ER) alpha and ER beta. Through the use of ER-deficient mice, we and others have begun to demonstrate the role of the two known receptors in modulating immune functional activities. Previous studies have shown that cells of the innate immune system have altered function (bactericidal capacity) and patterns of cytokine expression (increased proinflammatory cytokine expression) through amelioration of ER alpha signaling. In this study, we extend these studies to analysis of T cell differentiation and proliferation in APC-dependent and APC-independent in vitro assay systems. Our results demonstrate that ER alpha deficiency in splenic macrophages, but not CD11c(+) splenic dendritic cells pulsed with OVA significantly enhances proliferative responses and IFN-gamma production by transgenic OVA peptide-specific (OT-II) CD4(+) T cells when compared with Ag-pulsed APC from wild-type littermates. The addition of E-2 in this culture system did not significantly affect the production of IFN-gamma. An addition, when purified CD4(+) T cells from ER alpha-deficient and wild-type littermates were stimulated with anti-CD3/CD28 Ab in the absence of 1:21 there were no significant differences in IFN-gamma or IL-4 production. However, the addition of E-2 significantly increased IL-4 secretion, as well as increased GATA-3 mRNA levels from ER alpha-replete CD4(+) T cells, while this effect was abrogated in ER alpha-deficient CD4(+) T cells.