Immune tolerance toward the semiallogeneic fetus plays a crucial role in the maintenance of pregnancy. Myeloid‐derived suppressor cells (MDSCs) are innate immune cells characterized by their ability to modulate T‐cell responses. Recently, we showed that MDSCs accumulate in cord blood of healthy newborns, yet their role in materno–fetal tolerance remained elusive. In the present study, we demonstrate that MDSCs with a granulocytic phenotype (GR‐MDSCs) are highly increased in the peripheral blood of healthy pregnant women during all stages of pregnancy compared with nonpregnant controls, whereas numbers of monocytic MDSCs were unchanged. GR‐MDSCs expressed the effector enzymes arginase‐I and iNOS, produced high amounts of ROS and efficiently suppressed T‐cell proliferation. After parturition, GR‐MDSCs decreased within a few days. In combination, our results show that GR‐MDSCs expand in normal human pregnancy and may indicate a role for MDSCs in materno–fetal tolerance.

Tolerance induction toward the semiallogeneic fetus is crucial to enable a successful pregnancy; its failure is associated with abortion or preterm delivery. Skewing T cell differentiation toward a Th2-dominated phenotype seems to be pivotal in maternal immune adaption, yet underlying mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that mediate T cell suppression and are increased in cord blood of healthy newborns and in peripheral blood of pregnant women. In this study, we demonstrate that granulocytic MDSCs (GR-MDSCs) accumulate in human placenta of healthy pregnancies but are diminished in patients with spontaneous abortions. Placental GR-MDSCs effectively suppressed T cell responses by expression of arginase I and production of reactive oxygen species and were activated at the maternal–fetal interface through interaction with trophoblast cells. Furthermore, GR-MDSCs isolated from placenta polarized CD4⁺ T cells toward a Th2 cytokine response. These results highlight a potential role of GR-MDSCs in inducing and maintaining maternal–fetal tolerance and suggest them as a promising target for therapeutic manipulation of pregnancy complications.

Background: Sepsis is a major cause of death in neonates. Knowledge about epidemiology, risk factors, causative pathogens and outcome of neonatal sepsis is important to improve neonatal care. For Germany, only few data on neonatal sepsis in very low birth weight (VLBW) infants exist. Methods: Data from 14,926 preterm infants with birth weight <1500 g and gestational age between 22 0/7 weeks and 31 6/7 collected between January 2009 and December 2017 were analyzed for frequency of early-onset sepsis (EOS) and late-onset sepsis (LOS) and for causative pathogens. Risk factors for the development of EOS and LOS and outcomes after EOS and LOS were analyzed by multivariate logistic regression models. Results: EOS occurred in 1.1% of infants and LOS in 11.9%. Escherichia coli was the most common pathogen in EOS, coagulase-negative staphylococci in LOS. Multidrug-resistant organisms were detected in 8.4% of EOS and 3.9% of LOS cases. Risk factors for EOS were lower gestational age, intra-amniotic infection and spontaneous delivery. Risk factors for LOS were lower gestational age, small for gestational age, central lines, endotracheal ventilation and history of EOS. Both EOS and LOS were independently associated with adverse neonatal outcome. Conclusions: These data from a large German neonatal cohort confirm neonatal sepsis as the most common cause of morbidity and mortality in VLBW infants, as well as E. coli and coagulase-negative staphylococci as the most prevalent pathogens. Multidisciplinary approaches such as antibiotic stewardship, hygiene and feeding strategies are necessary to further reduce the burden of sepsis in VLBW infants.

Establishing and maintaining maternal‐fetal tolerance is essential for a successful pregnancy; failure of immunological adaptation to pregnancy leads to severe complications such as abortion or preterm delivery. Myeloid‐derived suppressor cells (MDSCs) are innate immune cells that suppress T‐cell responses, expand during pregnancy and thus may play a role in tolerance induction. Human leucocyte antigen G (HLA‐G) is a major histocompatibility complex (MHC) I molecule with immune‐modulatory properties, which is expressed during pregnancy. Here, we investigated the impact of HLA‐G on MDSCs accumulation and activation in pregnant women. We demonstrate that granulocytic MDSCs (GR‐MDSCs) express receptors for HLA‐G, namely immunoglobulin‐like transcript (ILT) 2 and 4, and that ILT4‐expression by GR‐MDSCs is regulated during pregnancy. Stimulation with soluble HLA‐G (sHLA‐G) increased suppressive activity of GR‐MDSCs, induced MDSCs from peripheral blood mononuclear cells (PBMCs) and led to phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and induction of indoleamine‐2,3‐dioxygenase (IDO) in myeloid cells. Effects of sHLA‐G on MDSC accumulation were mediated through ILT4. These results suggest an interaction between MDSCs and HLA‐G in humans as a potential mechanism for maintaining maternal‐fetal tolerance. Modulating MDSC function during pregnancy via HLA‐G might provide new opportunities for a therapeutic manipulation of immunological pregnancy complications.