Marilen Benner

MICROBIOTA AND ENDOMETRIAL HEALTH 155 6 UTERINE IMMUNITY DURING IMPLANTATION AND PLACENTATION AS A POSSIBLE INTERACTION PARTNER OF LOCAL MICROBIOTA Local immune cells belong to the factors known to influence extravillous trophoblast migration, and are therefore instrumental to maternal spiral artery remodeling (85). The immune system is intimately involved in all aspects of the reproductive process, particularly around the time of conception, and in the peri-implantation period (86). Different stages during the initiation of pregnancy hold specific immunologic challenges: to enable a healthy pregnancy, the maternal immune system must support the introduction of semen to allow fertilization, the initial contact of blastocyst and endometrium, and correct formation of the placenta (87). All of these processes are subjects of extensive study, and a comprehensive overview is beyond the scope of a single review. Natural killer (NK) cells, T cells and antigen presenting cells (APCs) are a common focus when investigating the immunology of pregnancy (88-95). We wish to highlight the importance of a tightly-regulated uterine immune environment that could potentially be affected by microbiota-induced factors. Recent discoveries on the interplay of the intestinal microbiome, their metabolites, and host immunity, give an impression of the vast impact that the endometrial microbiome could have (96-98). We outline here the implications of gut microbiota affecting cell types known to be important within the uterus. Lymphocytes involved in the peri-implantation period NK cells are the most abundant of immune cells in the endometrium representing ~ 70% of all hematopoietic cells present (99, 100). The term endometrial NK cells (eNK; or uterine NK cells; uNK cells) refers to NK cells in the non-pregnant endometrium, and decidual NK (dNK) cells residing in the placental membrane are phenotypically and functionally different from eNK cells or peripheral blood NK (pbNK) cells (100, 101). In the endometrium, the non-cytolytic and potent cytokine secretors, CD56 bright CD16 - NK cells, dominate. Only a small fraction of eNK cells belongs to the CD56 + CD16 + NK population specialized in killing infected cells (94, 102), contrary to the NK cell division in peripheral blood where the majority are CD56 + CD16 + . Throughout the female cycle, eNK cells continue to accumulate until the first half of gestation. Abnormal levels of NK cells, measured 20 days after ET, were shown to be associated with RIF (103). Direct involvement of eNK cells in implantation remains unclear, as successful implantation is possible in NK cell deficient mice (104). More evidence points towards an involvement of dNK cells in placenta-formation processes after initial implantation. However, an indirect role of the human CD56 bright CD16- eNK cells already during implantation cannot be neglected due to their high abundance and ability to secrete large amounts of cytokines, such as IFN- γ , tumor necrosis factor alpha (TNF α ), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 10 (IL-10) (102).