Myeloidderived suppressor cells: Escorts at the maternal-fetal interface.

Recently, a population of immature cells derived from myeloid progenitors, i.e., myeloid-derived suppressor cells (MDSCs), has entered the research spotlight ( 1 ). The molecular phenotypes of MDSCs are CD11b and Gr1 in mice, whereas it is HLA-DR low/− CD33 + in humans. These can be subdivided into the monocytic and granulocytic subtypes (M-MDSCs and G-MDSCs, respectively). Traditionally, they are defined as CD11b + Ly6C high Ly6G − and CD11b + Ly6G + Ly6C low in mice and CD11b + CD33 + CD14 + HLA-DR −/low and CD11b + CD33 + CD15 + /CD66 + HLA-DR − in humans, respectively ( 2 ). Recently, a number of novel markers and subsites of MDSCs have emerged, as shown in Table 1 . MDSCs exhibit significant heterogeneity because M-MDSCs and G-MDSCs can further differentiate into myeloid cells. Furthermore, it is difficult to distinguish them from mature monocytes and granulocytes based on immune molecular markers ( 30 ). In addition, a great deal of attention has been focused on the immunosuppressive function of MDSCs in tumors, autoimmune diseases, organ transplantation, and infectious diseases ( 31 – 34 ). In tumors, MDSCs inhibit the antitumor functions of T cells and natural killer (NK) cells and promote tumor progression by accelerating angiogenesis and cell invasion ( 2 , 35 , 36 ). Moreover, the proportion of MDSCs is closely associated with the clinical outcomes and therapeutic effects in patients with cancer ( 37 ). Although MDSCs are short-lived cells, they play crucial roles in many diseases. Phenotypes of myeloid-derived suppressor cells (MDSCs) in mice and humans. G-MDSCs, granulocytic myeloid-derived suppressor cells; M-MDSCs, monocytic myeloid-derived suppressor cells. The function of MDSCs during reproduction remains controversial. Embryo implantation, including the balance of immune cells at the maternal–fetal interface, reconstruction of the endometrial spiral arteries, and moderate invasion of trophoblasts, is a prerequisite for a successful pregnancy. Several studies have described how maternal–fetal tolerance is enhanced by accumulating MDSCs to suppress T-cell responses ( 38 – 40 ). Furthermore, the proportion of MDSCs was decreased in spontaneously aborting mice compared with controls, whereas their depletion resulted in the increased cytotoxicity of decidual NK cells ( 41 ). Even in infertile couples, the ratio of MDSCs in the peripheral blood of women who undergo in vitro fertilization (IVF) is considered an essential factor in predicting the outcomes of pregnancy ( 42 , 43 ). These findings might provide new insights into immune-related miscarriage and IVF failure. In addition, several studies have further demonstrated the accumulation and augmentation of MDSCs in newborn humans and mice ( 44 – 46 ). There is growing acceptance that MDSCs manipulate the maternal–fetal immune microenvironment to promote and sustain embryo implantation, protect the fetus during gestation, and keep the newborn healthy. In this review, we discuss the evidence concerning the association of MDSCs with embryo implantation, pregnancy complications, and newborn health and explore the potential relationship between MDSCs and the maternal–fetal immune microenvironment.

MDSCs play an immunosuppressive role in tumors ( 122 , 123 ) and a pro-inflammatory role in autoimmune diseases ( 124 , 125 ). Similarly, there is a shift from the early anti-inflammatory profiles that contribute to embryo implantation to a late pro-inflammatory cytokine profile that promotes fetal delivery ( 126 ). Notably, the MDSC counts decline rapidly in the peripheral blood of women after parturition ( 62 ). A transcriptome study that compared pregnancy-induced MDSCs to tumor-induced MDSCs revealed similar transcriptomes in both conditions. However, the antimicrobial-associated protein levels were higher in pregnancy-induced MDSCs ( 127 ). Furthermore, the MDSCs in neonates exhibited antimicrobial activity by secreting higher levels of cathepsin G, neutrophil cytosolic factor 1, S100 calcium-binding protein A8/A9, myeloperoxidase, lysozyme, neutrophil elastase, and lipocalin 2 ( 127 ). Similarly, the MDSCs in breast milk have also been found to protect infants from necrotizing enterocolitis and nosocomial bacterial infections ( 128 ). It appears that the MDSCs transferred from the mother to the fetus during delivery via the umbilical cord and breast milk harbor antimicrobial effects in infants. In addition to this protective function, MDSCs may also play a negative role in postnatal immune development, increasing susceptibility to infections in neonates. Estradiol levels are high in newborns, and there is estradiol-dominant MDSC recruitment and augmentation. Among infants, preterm babies show elevated estradiol levels in serum compared to full-term babies, while the MDSCs in umbilical cord blood also exhibit an abnormal increase ( 129 ). Premature infants are more susceptible to necrotizing enterocolitis, bronchopulmonary dysplasia, and sepsis ( 44 , 127 , 128 ). The underlying mechanisms may be associated with immune regulation activity and the immunosuppressive characteristics of MDSCs. During the neonatal period, a balance between immune attack and tolerance is extremely important ( 130 ). Generally, the immunosuppressive functions of umbilical cord blood MDSCs are to inhibit the differentiation and proliferation of Th1 and Th17 cells by producing Arg-1 and ROS and inducing cell–cell contact and to enhance the accumulation of immune regulatory Th2 cells and Tregs ( 131 – 134 ). Furthermore, MDSCs also suppress the cytotoxic NK cells through cell–cell interactions ( 131 ). When an anti-inflammatory immune reaction is activated (represented by Th2 and Treg hyperfunction), the newborn will not exhibit excessive immune attack when exposed to various antigens, bacteria, and viruses. However, in preterm infants, the high frequency of MDSCs enhances immune tolerance, leading to insufficient immune responses and neonatal diseases ( 46 , 134 – 136 ).

The immune environment at the maternal–fetal interface is complex and mysterious. MDSCs, as immunoregulatory cells with both pro-inflammatory and anti-inflammatory functions, are well documented to act as an escort throughout pregnancy (schematic diagram shown in Figure 1 ). Identifying the molecular mechanisms underlying the angiogenesis promotion and trophoblast implantation-inducing functions of these cells will enable precision therapy. During the window of implantation, intra-uterus transfusion of induced MDSCs or augment MDSCs in the decidua using multiple cytokines may provide tangible clinical benefits, such as elevate the live birth rate in recurrent embryo implantation failure, decrease pregnancy complications, and promote neonatal health. However, whether immunosuppression during pregnancy promotes the occurrence and progression of tumors remains uncertain. Further studies focusing on this aspect still need to be conducted. Schematic diagram. Myeloid-derived suppressor cells (MDSCs) secrete high levels of immunosuppressive products, including arginase-1 (Arg-1), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), and indoleamine-2,3-dioxygenase (IDO), and produce anti-inflammatory cytokines, such as interleukin 10 (IL-10) and transforming growth factor beta (TGF-β), with the ability to inhibit T-cell proliferation. In addition, MDSCs shift the T helper (Th) 1/Th2 cell and Th17/regulatory T cell (Treg) subsets to exert immunoregulation function. They also enhance uterine natural killer (uNK) cells to facilitate decidualization and placenta formation by downregulating perforin and granzyme B in the cytoplasm and NK group protein 2 D‐activating NK receptor (NKG2C) on the cell surface and promote angiogenesis and placental implantation through the VEGF and TIM3 pathway. During pregnancy, high levels of estrogen and trophoblasts may recruit, accumulate, or even induce the differentiation of MDSCs. MDSCs deficiency is considered to be associated with embryo implantation failure, spontaneous miscarriage, intrauterine growth restriction, and preeclampsia. Furthermore, MDSCs even play crucial roles to enhance immune tolerance in neonates.

BP, CH, HL, XN, and KW wrote the manuscript. CZ and HY revised the manuscript. All authors contributed to the article and approved the submitted version.