Supraphysiological estradiol promotes human T follicular helper cell differentiation and favours humoural immunity during in vitro fertilization

During pregnancy, humoural immunity is essential for protection against many extracellular pathogens; however, autoimmune diseases may be induced or aggravated. T follicular helper (Tfh) cells contribute to humoural immunity. The aim of this study was to test whether Tfh cell function can be manipulated via hormones. Seventy‐four women who underwent in vitro fertilization were recruited and divided into four groups: menstrual period (MP), controlled ovarian hyperstimulation (COH), embryo transfer (ET) and pregnant after embryo transfer (P). A flow cytometry analysis was performed to identify Tfh cells in peripheral blood mononuclear cells (PBMCs). Bioinformatics analysis revealed a possible pathway between Tfh and B cells. Enzyme‐linked immunosorbent assays were used to detect interleukin (IL)‐21 and IL‐6. The quantitative polymerase chain reaction was performed to quantify BCL‐6, BACH2, XBP‐1, IRF‐4 and G protein‐coupled (GP)ER‐1 mRNA expression. Compared with the MP group, the COH, ET and P groups showed more Tfh and B cells, as well as higher IL‐21, IL‐6, BCL‐6 and BACH2 expression. Furthermore, Tfh cell frequency in PBMCs, as well as serum IL‐21 and IL‐6 levels, were all positively correlated with serum estradiol (E(2)) levels; the B cell percentage also correlated positively with Tfh cells in PBMCs. Combined with the bioinformatics analysis, XBP‐1, IRF‐4 and GPER‐1 expression was related to E(2) levels, both in vivo and in vitro. We speculate that E(2) augments Tfh cells and favours humoural immunity. This study indicates that Tfh cell regulation may be a novel target in maintaining the maternal‐foetal immune balance.