Embryo implantation is an exceedingly complex, convoluted process of reproductive biology. An immunity homeostasis induced by maternal fetal cross-talk protects semi-allogeneic fetus from attacking by powerful maternal immune system. Pregnancy-induced immunomodulatory effects present in local of maternal-fetal interface as well as circulation of maternal system.
In the last decades, the contribution of MDSCs to maternal-fetal immunotolerance has been recognized [22, 23]. Their roles have been described in different situations, early and mid-term pregnancy, early miscarriage, the neonatal period and preeclampsia [24, 27, 29, 31]. Little is known, however, about the effects of MDSCs on the window of implantation (WOI) in RIF patients. To clarify this question, we investigated the patterns of MDSCs in peripheral blood from RIF women on the day of ET to determine whether MDSCs are involved in immunotolerance during WOI.
In present study, we found impressive impairments in frequency of peripheral blood MDSCs from women with RIF as compared to those from control group. These data are comparable to previous studies which described that the ratio of MDSCs among PBMCs showed a positive correlation with pregnancy rate in IVF patients [26]. MDSCs have been demonstrated to be one of the powerful immunosuppressive cells and tied up with maternal immune tolerance [32]. Köstlin and his group observed that healthy pregnant women have a significant accumulation of PMN-MDSCs in the blood during all stages of pregnancy [27]. Studies in human and mice report that a decreased percentage and activity of MDSCs in peripheral blood is associated with early miscarriage [9, 29, 33, 34]. In microenvironment, MDSCs secret iNOS to catabolize L-Arg to citrullin and produce NO which downregulates the expression of the TCR ζ chain on T cells hence restrain T cells activity [14]. As a pivotal antigen-recognition cells population in human, activated T cells may be a threat to the embryo expressing paternal antigen [35]. In agreement with these observations, when we considered measurement of intracellular NO as a biomarker of immunosuppressive potential for MDSCs [14] and compared those in each group, we found a significant reduction in intracellular NO produced by PMN-MDSCs from RIF patients. On the contrary, the levels of TCR ζ chain on CD4+ and CD8+Teffs are significantly upregulated in RIF patients. Moreover, the level of TCR ζ chain on CD4+ and CD8+Teffs was negatively correlated not only with the percentage of PMN-MDSCs, but also with the amount of NO produced by PMN-MDSCs.
MDSCs have been demonstrated to maintain maternal-fetal tolerance by inducing Foxp3 expression in CD4+CD25−T cells, hence expanding Tregs [30]. Tregs as a subpopulation of suppressor cells, express the transcription factor Foxp3 and play a critical role in preventing semi-allogeneic fetus from maternal immune system [36]. Anergia of conceptus-specific T cells during pregnancy relys on the persistent presence of Tregs [35]. Enhancement of Tregs in peripheral blood is concerned with a better IVF treatment outcome [37], whereas reduction of peripheral Tregs is associated with reproductive failure [38]. In line with these observations, we found an exhaustion of Tregs in RIF patients. However, the proportion of Tregs were not relevant to the proportion of MDSCs in this study. This may be due to the fact that Tregs can also be induced by hormones [39].
MDSCs require different signal molecules for their migration, proliferation and activation to suppress the immune response [15, 16]. CCL5 was reported to play a vital role in the recruitment and activation of MDSCs as well as the generation and mobilization of MDSCs [15]. Similar to these studies, we found a decrease of serum CCL5 in RIF patients as compared to controls. Moreover, our data showed that the level of serum CCL5 was positively correlated with PMN-DSCs. Using animal model, Bae et al. described that CCL5 may be involved in or promote the placental development [40]. Taken together, we would suggest that impaired CCL5 and MDSCs could be a cause for RIF. Furthermore, our finding revealed that RIF patients displayed a significantly lower concentration of serum TGF-β as compared to control women. As a major effective media, TGF-β was reported to be secreted by MDSCs and activate several signaling pathways in MDSCs, and consequently augment immunosuppressive capacity of MDSCs [14]. Meanwhile, as an important anti-inflammatory cytokine, TGF-β was significantly decreased in plasma from RIF patients [41]. Our study found that the concentration of serum TGF-β presents a positive correlation with the percentage of PMN-MDSCs. These discoveries provide further evidence that an appropriate amount of MDSCs may contribute to embryo implantation, whereas depletion of MDSCs is detrimental to embryo implantation.