Human Leucocyte Antigen G and Murine Qa-2 Are Critical for Myeloid Derived Suppressor Cell Expansion and Activation and for Successful Pregnancy Outcome

Abstract

During pregnancy, maternal immune system has to balance tightly between protection against pathogens and tolerance towards a semi-allogeneic organism. Dysfunction of this immune adaptation can lead to severe complications such as pregnancy loss, preeclampsia or fetal growth restriction. In the present study we analyzed the impact of the murine MHC class Ib molecule Qa-2 on pregnancy outcome in vivo. We demonstrate that lack of Qa-2 led to intrauterine growth restriction and increased abortion rates especially in late pregnancy accompanied by a disturbed trophoblast invasion and altered spiral artery remodeling as well as protein aggregation in trophoblast cells indicating a preeclampsia-like phenotype. Furthermore, lack of Qa-2 caused imbalanced immunological adaptation to pregnancy with altered immune cell and especially T-cell homeostasis, reduced Treg numbers and decreased accumulation and functional activation of myeloid-derived suppressor cells. Lastly, we show that application of sHLA-G reduced abortion rates in Qa-2 deficient mice by inducing MDSC. Our results highlight the importance of an interaction between HLA-G and MDSC for pregnancy success and the therapeutic potential of HLA-G for treatment of immunological pregnancy complications.

HIF‐1α targeted deletion in myeloid cells decreases MDSC accumulation and alters microbiome in neonatal mice

“…Tregs play an important role for regulating immune homeostasis and inflammation during microbiome establishment [69] and increased numbers of intestinal Tregs have been shown to protect from inflammatory diseases like asthma or colitis, especially if induced during the neonatal period [70, 71]. We and others showed that Tregs are induced by MDSC [14, 20, 72]. In the data presented here, it remains unclear whether the decreased Treg numbers in neonatal Hif1a loxP/loxP LysM Cre+ mice are due to decreased MDSC numbers or the altered microbiome.…”

“…Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells that accumulate during pregnancy in the maternal and fetal organism and contribute to maternal-fetal tolerance [14][15][16][17][18]. In neonates, MDSC influence T-cell and monocyte functions [19,20] and appear to play a role in inflammation control during the neonatal period [21].…”

“…The transcription factor hypoxia-inducible factor 1α (HIF-1α) plays an important role in MDSC accumulation and activation [14,22,23]. Our group has shown that a lack of HIF-1α in myeloid cells (Hif1a loxP/loxP LysM Cre+) leads to a decreased MDSC accumulation during pregnancy and affects suppressive activity of MDSC [24].…”

Myeloidderived suppressor cells: Escorts at the maternal–fetal interface

“…Estradiol alone may induce an increased VEGF expression in MDSCs to promote maternal uterine spiral arteries and placental development in rats ( 88 , 96 ). Similar to the above-mentioned hormones, human leukocyte antigen G (HLA-G), a molecule secreted and expressed by several cells in the maternal–fetal interface, is also a crucial player in MDSC accumulation in the decidua ( 97 ). It usually binds to immunoglobulin-like transcript 4 and induces the expansion and differentiation of MDSCs in peripheral blood mononuclear cells through STAT3 signaling ( 98 , 99 ).…”

Depletion of Ly6G-Expressing Neutrophilic Cells Leads to Altered Peripheral T-Cell Homeostasis and Thymic Development in Neonatal Mice

“…GR-MDSC expand under various pathological conditions, usually leading to harmful immunosuppression, especially by targeting T-cells [12]. In recent years, however, it has become more and more clear that GR-MDSC also accumulate physiologically during pregnancy in the maternal and fetal organism [9,13], facilitating maternal-fetal tolerance [14][15][16] and modulating neonatal immune responses [17][18][19]. GR-MDSC carry the same surface markers as neutrophils and can be distinguished from them only by their suppressive capacity and-in humans-by their lower density [20,21].…”