trogen has diverse effects on inflammation and immune responses. That pregnancy is associated with remission of some autoimmune diseases and exacerbation of others suggests that physiological fluctuation in estrogen levels could affect the immune responses in humans. However, the molecular basis for these phenomena is poorly understood. We hypothesized that fluctuations of estrogen levels modulate intracellular signaling for immune responses via estrogen receptors (ERs). In reporter assays, 17␤-estradiol (E2) at a physiologically high concentration increased the activity of NF-B in Jurkat cells stimulated by PMA/ionomycin or TNF-␣. Overexpression and RNA interference experiments suggested that the effects were mediated through ER␤. Immunoprecipitation assay showed that both ER␣ and ER␤ are directly associated with NF-B in the cell nucleus. Using chromatin immunoprecipitation assay, we confirmed that ER␣ and ER␤ associated with NF-B and steroid hormone coactivators at the promoter region of NF-B regulated gene. Considering that NF-B regulates the expression of various genes essential for cell growth and death, estrogen could regulate the fate of T cells by affecting the activity of NF-B. To determine whether E2 alters the fate of T cells, we investigated E2 actions on T cell apoptosis, a well-known NF-Bmediated phenomenon. E2 increased apoptosis of Jurkat cells and decreased that of human peripheral blood T cells. Our results indicate that E2 at a physiologically high concentration modulates NF-B signaling in human T cells via ER␤ and affects T cell survival, suggesting that these actions may underlie the gender differences in autoimmune diseases. sex hormone; autoimmune disease; coactivator; transcription factor MANY AUTOIMMUNE DISEASES ARE more prevalent in women than in men (42, 44). Some autoimmune diseases, such as systemic lupus erythematosus (SLE), frequently show exacerbation during pregnancy (42), and in this regard, patients with SLE often have high serum estrogen concentrations (27). These clinical facts led us to hypothesize that fluctuation in estrogen levels could modulate autoimmune responses.Baseline estrogen concentrations do not differ significantly between men and women. However, the serum concentration of 17␤-estradiol (E2), the most potent and predominant estrogen in human serum, increases from baseline 10 pM to 40 nM during pregnancy (45). Estrogen has diverse effects on inflammatory and immune systems (8,33), and the physiological fluctuation in estrogen level could affect the immune responses in humans (5). However, the molecular basis for these phenomena is poorly understood.