Part F: Pathways for Activating Implantation Tolerance in Early Pregnancy

Immune attack of the conceptus at implantation is suppressed predominantly by the actions of T regulatory (Treg) cells and deficiency in these cells is linked with unexplained infertility, miscarriage, and preeclampsia. The pathways by which Treg cells originate and the factors that control their ontogeny and recruitment into the implantation site are now being explored. Experiments in mice show that male seminal fluid plays a pivotal role in expanding the size of the inducible Treg cell pool after every coital event, in readiness for potential pregnancy. The cytokine TGFβ which induces Treg cells, as well as male alloantigens, are abundant in seminal fluid and exposure of female tissues to seminal fluid initiates a sequence of events causing Treg cells to be recruited into the endometrial tissue. This pathway depends on female dendritic cells that take up seminal fluid antigens and traffic to local lymph nodes to cross-present antigens to both CD8+ and CD4+ T cells, which in turn circulate via the blood to be sequestered back into the endometrium. Thus, agents of both male and female origin in the peri-conceptional environment are important determinants of maternal immune tolerance and ultimately the progression and success of pregnancy. Components of this pathway are present in the human genital tract, and recent studies show seminal fluid activates immune cells in the cervix and seminal fluid TGFβ together with E-series prostaglandins play an important role in triggering this response. Defining how mechanisms of tolerance induction occur in women will be important for informing development of new therapies for pathologies of pregnancy that have an immune aetiology.

Keywords: Cytokine, Treg cells, tolerance, embryo implantation, pregnancy, seminal fluid.