The Link Between Seminal Cytokine Interleukin 18, Female Circulating Regulatory T Cells, and IVF/ICSI Success

Seminal plasma (SP) is thought to be a crucial factor which affects the expansion of regulatory T cells (Tregs) in female reproductive tract during embryo implantation. We propose that seminal transforming growth factor (TGF) β1 is responsible for local accumulation of circulating Tregs, which manifests as changes in Treg frequency in peripheral blood, whereas seminal interleukin (IL) 18 interferes with TGF-β1-dependent cellular reactions. The purpose of the present study is to determine whether the frequency of circulating Tregs is associated with the levels of seminal cytokines and pregnancy establishment in women exposed to partner’s SP during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle. Twenty-nine women were exposed to SP via timed intercourse before the day of ovum pickup (day-OPU) and also subjected to intravaginal SP application just after OPU. Measurements of seminal TGF-β1 and IL-18 were made by FlowCytomix technology. The percentage of CD4 + CD25 + CD127 low+/- Tregs among total circulating CD4 + T cells was determined by flow cytometry and the difference between Treg values on the day of embryo transfer and day-OPU was calculated. The percentage of Tregs on the day-OPU, identified as a predictive factor of clinical pregnancy after IVF/ICSI, showed a positive correlation with IL-18 concentration and content of this cytokine per ejaculate ( P <.001 and P <.004, respectively) and negative correlation with the TGF-β1/IL-18 ratio ( P <.014).These findings indicate that the adverse effect of seminal IL-18 excess on implantation may be realized by the prevention of postcoital TGF-β1-related migration of circulating Tregs, which clearly manifests as elevated level of Treg frequency in peripheral blood.