There was no significant difference in the immune cell population in 6C8-week-old male and female mice (Supplementary Fig

There was no significant difference in the immune cell population in 6C8-week-old male and female mice (Supplementary Fig.?1). resulted in an increased proportion of TFH cells and germinal center (GC) responses. In addition, 17-estradiol (E2) treatment decreased TFH responses in wild-type mice and suppressed the mRNA expression of Bcl-6 and IL-21. Finally, we confirmed that the production of high-affinity antigen-specific antibodies and isotype class switching induced by NP-conjugated ovalbumin immunization were elevated in CD4-ER KO mice under sufficient estrogen conditions. These results collectively demonstrate that the female sex hormone receptor ER inhibits the TFH cell response and GC reaction to control autoantibody production, which was related to estrogen signaling and autoimmunity. strong class=”kwd-title” Subject terms: Autoimmunity, Follicular T-helper cells Introduction Estrogen is the predominant hormone in females and plays important roles in the endocrine and reproductive systems1. The function of estrogen is mediated by ER and ER, and both receptors are expressed in most tissues2. Although their principle role has been associated with physiological events, such as the menstrual cycle and menopause, previous studies have shown that ER signaling is also involved in the regulation of immune cell functions3C5. The role of ER has been studied in A-381393 effector T cells, including Th1, Th2, Th17, and Treg cells. ER has been reported to increase Th2 and Treg cells in mice by interacting with transcription factors, such as GATA3 and Foxp36C8. Recently, ER has been shown to directly bind to the promoter region of RORt to suppress Th17 differentiation and function9,10. Furthermore, estradiol treatment prevented experimental autoimmune encephalomyelitis (EAE) disease progression by inhibiting the infiltration of Th1 and Th17 cells, while mice with ER-deficient T cells failed to suppress the disease pathogenesis11. These previous studies revealed significant roles of estrogen and estrogen receptors in T cell immunity and autoimmune disease. Previous studies have suggested that TFH cells stimulate autoantibody production in germinal centers (GCs), which leads to the development of autoimmune disease12C15. Spontaneous GC formation and autoantibody production was observed in A-381393 experimental SLE models, such as NZB and MRL/lpr mice16,17. Sanroque mice showed autoimmune lupus symptoms with an excessive TFH cell count BAX and spontaneous GC formation18. IL-21, which is an important cytokine for TFH differentiation and function, was increased in patients with SLE compared with healthy controls19, and circulating TFH cells, which have been previously shown to be related to disease severity, were increased in patients with SLE20. Therefore, TFH cell functions that stimulate autoantibody production may be related to the onset or lead to the development of autoimmune disease, and thus, the regulatory mechanism of the TFH response should be studied to further understand autoimmunity. Most autoimmune diseases predominantly occur in women because estrogen signaling contributes to sex-dependent immunity, which regulates T cell functions and autoimmune disease21C23. Previous ER-deficient mouse studies have reported increased severity of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and EAE11,24C26. Here, A-381393 we hypothesized the possible regulatory role of ER in TFH cell function and autoantibody response, which could be related to autoimmune disease. We analyzed CD4-ER knockout (KO) mice, which spontaneously developed mild autoimmune phenotypes with increased autoantibodies and TFH cells. We further confirmed that ER-mediated estrogen signaling suppressed TFH and GC B cell formation, which leads to the production of high-affinity antibodies and isotype-class switching. Our study reveals roles of ER in T.