Blood monocyte-derived macrophages invading the alveolus encounter pulmonary surfactant, a phospholipoprotein complex that changes composition during lung development. We tested the hypothesis that ...characteristic phosphatidylcholine (PC) components differentially influence macrophage phenotype and function, as determined by phagocytosis of green fluorescent protein-labeled Escherichia coli and αCD3-induced T cell proliferation. Human macrophages were exposed to surfactant (Curosurf®), to two of its characteristic phosphadidylcholine (PC) components (dipalmitoyl-PC and palmitoylmyristoyl-PC), and to a ubiquituous PC (palmitoyloleoyl-PC) as control. Interaction of Curosurf and PC species with macrophages was assessed using Lissamine™-dihexadecanoyl-phosphoethanolamine-labeled liposomes. Curosurf and both saturated surfactant PC species downregulated CD14 expression and upregulated CD206. HLA-DR and CD80 were upregulated by Curosurf and palmitoylmyristoyl-PC, whereas dipalmitoyl-PC showed no effect. The latter upregulated TLR2 and TLR4 expression, whereas Curosurf and palmitoylmyristoyl-PC had no effect. PC species tested were incorporated in comparable amounts by macrophages. Curosurf and PC species inhibited phagocytosis of E. coli. Scavenger receptor CD36, CD68, SR-A, and LOX-1 mRNA expression was upregulated by Curosurf, whereas PC species only upregulated SR-A. Curosurf and palmitoylmyristoyl-PC inhibited αCD3-induced T cell proliferation by 50%, whereas dipalmitoyl-PC and palmitoyloleoyl-PC showed no effect. These data identify individual surfactant PC species as modifiers of macrophage differentiation and suggest differential effects on innate and adaptive immune functions.
Term and especially preterm neonates are much more susceptible to serious bacterial infections than adults. But not only the susceptibility to infection is increased in neonates, but also their risk ...for developing post-inflammatory diseases such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL). This may be due to an impaired ability to terminate inflammation. In the study presented here, we aimed to investigate the proliferative response and the expression of immune-checkpoint molecules (ICM) and activation markers on neonatal T-cells in comparison to adult T-cells with the hypothesis that an increased activation of neonatal T-cells may contribute to the failure of inflammation resolution observed in neonates. We show that neonatal CD4
+
and CD8
+
T-cells show an increased proliferative capacity and an increased expression of activation markers compared to adult T-cells upon stimulation with OKT3 as well as a decreased expression of ICM, especially PD-L1 on their surface. This decreased expression of PD-L1 by neonatal T-cells was also observed after stimulation with GBS, but not after stimulation with
E. coli
, the two most important pathogens in neonatal sepsis. Expression of the T-cell receptor CD3 and the co-stimulatory molecule CD28 did not differ between adult and neonatal T-cells upon bacterial stimulation. Decreased expression of ICM upon T-cell activation may be a reason for the increased risk of neonates to develop post-inflammatory diseases.
Neonatal sepsis is a leading cause of perinatal morbidity and mortality. In comparison to adults, neonates exhibit a higher susceptibility to infections. Myeloid-derived suppressor cells (MDSCs) are ...myeloid cells with suppressive activity on other immune cells accumulating during foetal life and controlling inflammation in neonates. Most studies investigating the mechanisms for MDSC-mediated immune suppression have been focused on T-cells. Thus far, little is known about the role of MDSC for monocyte function.
The impact of human cord blood MDSCs (CB-MDSCs) on monocytes was investigated in an in vitro model. CB-MDSCs were co-cultured with peripheral blood mononuclear cells and monocytes were analysed for expression of surface markers, T cell stimulatory and phagocytic capacity, as well as the production of intracellular cytokines by flow cytometry.
CB-MDSCs increased the expression of co-inhibitory molecules and decreased the expression of major histocompatibility complex class II molecules on monocytes, leading to an impaired T-cell stimulatory capacity. Upon bacterial stimulation, expression of phagocytosis receptors, phagocytosis rates and production of tumor necrosis factor-α by monocytes was diminished by CB-MDSCs.
We show that CB-MDSCs profoundly modulate monocyte functions, thereby indirectly impairing T-cell activation. Further research is needed to figure out if MDSCs could be a therapeutic target for inflammatory diseases in neonates like neonatal sepsis.
•GGranulocytic myeloid-derived suppressor cells (GR-MDSC) isolated from the peripheral blood of pregnant women release exosomes.•Exosomes released by GR-MDSC from pregnant women inhibit T-cell ...proliferation.•Exosomes released by GR-MDSC from pregnant women polarize T-helper (Th) cells towards a Th2 cytokine response and induce the generation of regulatory T-cells (Tregs).•Exosomes released by GR-MDSC from pregnant women inhibit lymphocyte cytotoxicity.•Exosomes released by GR-MDSC from pregnant women contain Arginase I (ArgI) and inducible NO-synthase (iNOS).
Immunological pregnancy complications are a main challenge in reproductive medicine. Mechanisms regulating the adaptation of the maternal immune system to pregnancy are incompletely understood and therapeutic options limited. Myeloid derived suppressor cells (MDSC) are immune-modulatory cells expanding during healthy pregnancy and seem to play a crucial role for maternal-fetal tolerance. Recent studies showed that exosomes produced by MDSC have immune-modulatory effects corresponding to their parental cells under different pathological conditions. Here, we investigated immunological effects of exosomes of GR-MDSC during pregnancy. Isolated GR-MDSC exosomes from peripheral blood of pregnant women were tested for functionality in different in vitro assays. We show that GR-MDSC exosomes exhibited profound immune-modulatory effects such as suppression of T-cell proliferation, T helper 2 (Th2)-cell polarization, induction of regulatory T-cells and inhibition of lymphocyte cytotoxicity. Our results confirm that MDSC-derived exosomes functionally correspond to their parental cells and identify them as an interesting therapeutic target for immunological pregnancy complications.
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.
Abstract Purpose The optimal surgical management of extremely (ELBW) and very low-birth-weight (VLBW) neonates with esophageal atresia and distal tracheoesophageal fistula (EA/TEF) (Gross type C) is ...still debated. The aim of this study was to evaluate the surgical outcome of primary repair in these patients and compare it to ≥ 1500 g neonates. Methods Medical records of neonates with repaired EA from 2002 to 2016 were reviewed. Results 4 ELBW, 7 VLBW, and 24 ≥ 1500 g infants had type C EA/TEF and underwent primary repair. Anastomotic leakage occurred in 0% ELBW, 0% VLBW and 8.3% ≥ 1500 g patients and anastomotic stricture in 25% ELBW, 28.5% VLBW and 37.5% ≥ 1500 g patients. 50% ELBW, 14.2% VLBW and 20.8% ≥ 1500 g patients underwent secondary fundoplication. One patient of the VLBW group and one patient of the ≥ 1500 g group died postoperatively of causes not related to EA/TEF. Conclusions In extremely and very low-birth-weight neonates with type C EA/TEF surgical outcome after primary repair is comparable to the outcome in ≥ 1500 g neonates. Primary repair can be performed in most of these patients and staged repair can be restricted to unstable patients.
Summary
Infections are a leading cause of perinatal morbidity and mortality. The outstandingly high susceptibility to infections early in life is mainly attributable to the compromised state of the ...neonatal immune system. One important difference to the adult immune system is a bias towards T helper type 2 (Th2) responses in newborns. However, mechanisms regulating neonatal T‐cell responses are incompletely understood. Granulocytic myeloid‐derived suppressor cells (GR‐MDSC) are myeloid cells with a granulocytic phenotype that suppress various functions of other immune cells and accumulate under physiological conditions during pregnancy in maternal and fetal blood. Although it has been hypothesized that GR‐MDSC accumulation during fetal life could be important for the maintenance of maternal–fetal tolerance, the influence of GR‐MDSC on the immunological phenotype of neonates is still unclear. Here, we investigated the impact of GR‐MDSC isolated from cord blood (CB‐MDSC) on the polarization of Th cells. We demonstrate that CB‐MDSC inhibit Th1 responses and induced Th2 responses and regulatory T (Treg) cells. Th1 inhibition was cell‐contact dependent and occurred independent of other cell types, while Th2 induction was mediated independently of cell contact through expression of ArgI and reactive oxygen species by CB‐MDSC and partially needed the presence of monocytes. Treg cell induction by CB‐MDSC also occurred cell‐contact independently but was partially mediated through inducible nitric oxide synthase. These results point towards a role of MDSC in regulating neonatal immune responses. Targeting MDSC function in neonates could be a therapeutic opportunity to improve neonatal host defence.
In the present study we showed that cord blood myeloid‐derived suppressor cells (CB‐MDSC) polarized T helper (Th) cells towards a Th2 response and induced regulatory T cells. Effects of CB‐MDSC on Th cells were all mediated through different mechanisms. Differentiated targeting of MDSC effector functions could be an option for selective modification of neonatal T‐cell responses and improved neonatal host defence.
PDF
