Marilen Benner

UTERINE LYMPHOCYTES GAIN EXPERIENCE DURING PREGNANCY 35 2 remains poorly defined (13). We observed mainly effector memory (EM) and central memory (CM) T cells at the end of pregnancy, and they were thus more experienced and differentiated than T cells from pre-pregnancy endometrium. This suggests that over the course of pregnancy, T cells at the fetal-maternal interface may differentiate. After implantation of a blastocyst, endometrium will modify to decidua, and cells of fetal origin will come in to contact with lymphocytes at the maternal-fetal interface. This contact might differentiate endometrial T cells towards a phenotype as seen in decidual tissue, as suggested by our in vitro assay. The target specificity of the T cells and exact trigger for this differentiation is unclear, but multiple triggers have been suggested to play a role, including fetal alloantigens like major histocompatibility complex antigens (MHC) (HLA-C in humans) (2, 4, 38), minor histocompatibility antigens (mHags) (6, 39), and/ or pathogen-derived antigens (40). In accordance, Tilburgs et al. previously reported that in addition to the lower numbers of naive T cells in decidual tissue, mainly EM and few CM CD8 + T cells were present in term decidua (35). Pregnancy induces local enrichment of Treg at the fetal-maternal interface (30, 41). These Treg play an important role in tolerance to the semi-allogeneic fetus and pregnancy in mice, since mouse studies showed that depletion of CD25 + Treg resulted in gestation failure in allogeneic pregnancies (20-22). We showed that the percentage of CD4 + CD25 high CD127 - Treg was higher in decidua than in endometrium, suggesting a more tolerogenic environment during pregnancy. As previously reported by our group(27), no difference in the percentage of Treg in MMC and PBMC samples was observed. The increased percentage of Treg we found in term decidual tissue is comparable to percentages found in other studies (30). Based on the expression of CD45RA and CD25, human CD4 + T cells can be separated into differentiated Treg and naive Treg (36). We showed that term decidua contained more differentiated Treg than endometrium, while the presence of naive Treg was lower. In peripheral blood, these differentiated Treg were shown to be derived from recently activated naive Treg and were suggested to be the main effectors of suppression (36). In mice, it was shown that during the course of pregnancy Treg will acquire a protective regulatory memory phenotype to fetal antigen. These memory Treg persist after pregnancy and re-accumulate rapidly in a subsequent pregnancy (42). A similar phenomenon thus may take place in the uterus during human pregnancy. Not only Treg, but the overall balance between Th1, Th2, Th17, and Treg cells is suggested to be of relevance for successful pregnancy (14). Th subsets can be classified by the production of particular cytokines by T cells, or by the expression of different chemokine receptors on T cells (37). Using a classification based on chemokine receptor expression patterns, we found that both term decidua and pre-pregnancy endometrium held relatively more Th1 cells, and less Th2 cells compared to peripheral blood. Our results thus showed that in the uterine environment, there is a preference of Th1 over Th2 cells. The same trend was also seen in first trimester decidua (43). This suggests that this preference is already present in pre-pregnancy endometrium