Marilen Benner

UTERINE LYMPHOCYTES GAIN EXPERIENCE DURING PREGNANCY 27 2 INTRODUCTION Pregnancy requires a complex interplay of immune cells. Maternal lymphocytes need to accommodate the semi-allogeneic fetus and still maintain robust immune reactivity against pathogens. The barrier between the semi-allogeneic fetus and the maternal immune system is the placenta. At this fetal-maternal interface, maternal lymphocytes of the decidua come into close contact with cells of fetal origin, i.e. trophoblast cells. This contact occurs at two different sites, between invading trophoblast cells and the decidua basalis, which is the site of implantation, and chorionic trophoblast cells and the decidua parietalis, which are part of the membranes surrounding the fetus (1). These trophoblast cells have restricted HLA expression (HLA-C, HLA-E, and HLA-G). Direct response to fetal allogeneic HLA is primarily via HLA-C, but also indirect presentation of fetal antigens by maternal APCs can elicit an anti-fetal maternal leukocyte response (2-6). This restricted immune recognition makes that the uterine immune cell composition and phenotype is different from other mucosal sites (1). Each month, during the menstrual cycle, the uterus prepares itself for pregnancy by a large influx of leukocytes in the endometrium. When implantation takes place, the number of leukocytes increases even further. Without implantation, the endometrial lining and its leukocytes are shed during menstruation (7). Natural killer (NK) cells are abundantly present in the human endometrium (8, 9). Endometrial NK cells increase in number during the menstrual cycle, reaching a peak in the late secretory phase. If implantation occurs, endometrium will transform into decidua and the number of endometrial NK cells will increase even further and will make up 70% of the decidual leukocytes during the first trimester. These uterine NK cells are different from NK cells found in peripheral blood. They are characterized as being CD56 bright CD16 - , while NK cells found in peripheral blood are mainly CD56 dim CD16 + (8, 10). Decidual NK cells produce specific cytokines and angiogenic factors to regulate invasion of fetal trophoblast cells and spiral artery remodeling (7, 10). Besides NK cells, also T cells are a major cell population in the endometrium and decidua (8, 11). Decidual T cells differ from peripheral T cells by expression of activation markers such as CD45RO, CD69, HLA-DR, and CD25 (12), but their function and mechanism of fetus-specific immune recognition remains poorly defined (13). It has long been thought that maternal tolerance towards fetal alloantigens was established by a predominance of T helper type 2 (Th2) immunity over Th1 immunity during pregnancy. However, this Th1/Th2 paradigm was found insufficient, since both Th1 and Th2 dominant immunity was observed in pregnancy complications (14). Th17 cells produce IL-17 and mediate the induction of inflammation (15). Higher levels of Th17 cells were found in women suffering from recurrent pregnancy loss and preterm delivery (16-18). In contrast, mouse studies revealed that regulatory T cells (Treg) are essential for promoting immune tolerance towards the fetus, and activation of Treg is needed for pregnancy success,