Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype

Abstract

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.

Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy

“…In both cases, pregnancy and worsened outcomes of HIV infection, the immune suppression was associated with LDG-mediated impaired T cell responses (66, 70). Alternatively, other studies have described increases in the proportion of granulocytic myeloid-derived suppressor cells (GR-MDSCs) in healthy pregnancies, where they seem to be responsible for the observed suppression of some immune reactions, along with the induction of Tregs (71, 72). The GR-MDSCs subset is also characterized by a low-density and immature phenotype with high expression of CD11b, CD15, CD33 and CD66b molecules, and so it is seemingly difficult to be able distinguish them from the neutrophil subset within the LDG fraction (61, 73, 74).…”

Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period

“…MDSC have been described widely to play an important role for immune regulation during pathological processes such as tumours, infections or transplant reactions [16,17,21,24,32,33]; recently, however, increasing evidence has emerged revealing that they also control immune adaptation to pregnancy and contribute to maternal-fetal tolerance both maternally and fetally [12][13][14][15]19,34,35]. Until now, little is known about their impact on immune regulation in neonates, and especially in preterm infants.…”

“…In humans, MDSC can be divided into two subgroups: granulocytic MDSC (GR-MDSC) expressing granulocytic lineage markers CD15 and/or CD66b, and monocytic MDSC (MO-MDSC) expressing the monocytic antigen CD14. GR-MDSC, but not MO-MDSC, accumulate during pregnancy in both mother and fetus [12][13][14][15]19], and are supposed to play a role in mediating maternal-fetal tolerance. A phenotypical difference between GR-MDSC and mature granulocytes is the lower density of GR-MDSC, sedimenting with mononuclear cells (MNC) after density gradient centrifugation.…”

Hypothesis about Transdifferentiation As Backbone of Malignancy

“…Released exosomes along with secretions rich in factors of the VEGF family, including the PGF, trigger activation and recruitment of vascular endothelial growth factor receptor 1-expressing myeloid cells that will locally develop favorable places for metastatic colonizing (53). Trophoblast as well as cancer cells interact with the host organism to promote the recruitment of myeloid-derived suppressor cells that are effectors of immune tolerance (54, 55). …”