Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T‐cell responses

Abstract

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.Keywords: Myeloid-derived suppressor cells (MDSCs) r Reproductive immunology r T cells r Tolerance Additional supporting information may be found in the online version of this article at the publisher's web-site

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

“…The heterogeneous phenotype of plaGR-MDSCs and cord blood GR-MDSCs confirms observations from others that GR-MDSCs are a heterogeneous cell population containing different developmental states and that the expression of surface markers strongly depends on environmental factors (14,20,23).…”

“…The current state of knowledge is that MDSCs are a heterogeneous population of myeloid progenitor cells that can be subdivided at least into a GR-MDSC and a monocytic MDSC subset. In our previous study we found an increase in GR-MDSCs in peripheral blood of pregnant women whereas numbers of monocytic MDSCs were similar in pregnant and nonpregnant women (23). In the present study, we therefore focused on GR-MDSCs.…”

“…Recently, our group showed that they are also increased during pregnancy in fetal and maternal blood (22,23), and we hypothesized that they could play a role in maintaining pregnancy and mediating maternal-fetal tolerance. We now describe, to our knowledge for the first time, MDSCs in human placenta and show that 1) GR-MDSCs accumulate at the maternalfetal interface, but are diminished in placentas from women with spontaneous abortions; 2) plaGR-MDSCs show a differentiated phenotype, are mainly located in the decidual placenta, and are of maternal origin; and 3) plaGR-MDSCs efficiently suppress T cell proliferation by ArgI and production of ROS, 4) become activated at the maternal-fetal interface through an interaction with trophoblast cells via CXCR4, and 5) may polarize T cells toward a Th2 phenotype.…”

“…Recently, we showed that GR-MDSCs also expand in cord blood of healthy newborns (22) and in peripheral blood of pregnant women (23) and that these cells are effective modulators of T and NK cell responses, indicating a potential role of GR-MDSCs in physiological immune regulation during pregnancy.…”

Human trophoblast cells induced MDSCs from peripheral blood CD14+ myelomonocytic cells via elevated levels of CCL2

“…CD14 1 HLA-DR 2/low cells, a subset of CD14 1 myelomonocytic cells, exhibit potent suppressive activity 6 , and these cells are monocytic myeloid-derived suppressor cells (MOMDSCs) 7,8 , which have emerged as key immune modulators orchestrating lymphocyte responses. There is increasing interest in the role of MDSCs as tolerance-inducing cells during pregnancy 9,10 . Although studies have suggested that isolated myeloid cells or MDSCs from the peripheral blood of pregnant women could efficiently suppress T-cell proliferation, information concerning the mechanisms governing MDSCs mobilization, particularly during the implantation and invasion of trophoblast cells, is lacking.…”