Myeloid-derived suppressor cells are essential for maintaining feto-maternal immunotolerance via STAT3 signaling in mice

Abstract

Maternal immune system tolerance to the semiallogeneic fetus is essential for a successful pregnancy; however, the mechanisms underlying this immunotolerance have not been fully elucidated. Here, we demonstrate that myeloid-derived suppressor cells play an important role in maintaining feto-maternal tolerance. A significant expansion of granulocytic myeloid-derived suppressor cells was observed in multiple immune organs and decidual tissues from pregnant mice. Pregnancy-derived granulocytic myeloid-derived suppressor cells suppressed T cell responses in a reactive oxygen species-dependent manner and required direct cell-cell contact. Mechanistic studies showed that progesterone facilitated differentiation and activation of granulocytic myeloid-derived suppressor cells, mediated through STAT3 signaling. The STAT3 inhibitor JSI-124 and a specific short hairpin RNA completely abrogated the effects of progesterone on granulocytic myeloid-derived suppressor cells. More importantly, granulocytic myeloid-derived suppressor cell depletion dramatically enhanced the abortion rate in normal pregnant mice, whereas adoptive transfer of granulocytic myeloid-derived suppressor cells clearly reduced the abortion rate in the CBA/J X DBA/2J mouse model of spontaneous abortion. These observations collectively demonstrate that granulocytic myeloid-derived suppressor cells play an essential role in the maintenance of fetal immunotolerance in mice. Furthermore, our study supports the notion that in addition to their well-recognized roles under pathologic conditions, myeloid-derived suppressor cells perform important functions under certain physiologic circumstances.

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.…”

“…Before birth, GR-MDSC may play a critical role in maintaining maternal-fetal tolerance [12,13,34,35], being beneficial for fetal life, whereas postnatally elevated GR-MDSC numbers may contribute to postnatal immunosuppression and susceptibility to infections. Before birth, GR-MDSC may play a critical role in maintaining maternal-fetal tolerance [12,13,34,35], being beneficial for fetal life, whereas postnatally elevated GR-MDSC numbers may contribute to postnatal immunosuppression and susceptibility to infections.…”

“…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.…”

“…Potential mechanisms of postnatal immunosuppression are a bias of T helper (Th) cell responses towards Th2 and an accumulation of immunemodulatory cells such as regulatory T cells (T regs ), regulatory B cells (B regs ) and CD71 positive erythroid cells [7,10,11]. Recently, we and others have described myeloidderived suppressor cells (MDSC) as potential immune regulators during pregnancy [12][13][14][15].…”

Neutrophil Diversity in Health and Disease

“…cancer, infectious diseases, autoimmunity, and obesity) [57] (Box 2 and section on Neutrophil Diversity and Heterogeneity in Cancer). During mouse pregnancy, they are increased in the circulation of pregnant females relative to non-pregnant females, migrate to the uterus, and can drive CD4 + and CD8 + T cell suppression, thus permitting embryo implantation and successful pregnancy; indeed, depletion of these neutrophils using anti-Gr-1 antibodies caused CD3 + T cell infiltration in the uterus and resorption of the conceived embryo [58,59]. Mechanistically, such T cell suppression by PMN-MDSCs was reported to be driven by downregulation of L-selectin (CD62L) Box…”