Abstract
Myeloid-derived suppressor cells (MDSC), especially polymorphonuclear MDSC (PMN-MDSC), accumulate in maternal-fetal interface during pregnancy and are involved in the maintenance of immune tolerance. Decreased PMN-MDSC is associated with pregnancy complications such as unexplained recurrent pregnancy loss (URPL). In the present study we showed decreased PMN-MDSC in the URPL group compared with the normal pregnancy (NP) group, and PMN-MDSC was the major subset of MDSC in human decidua with potent immune suppression activity. We then performed gene expression profile and found that human decidual PMN-MDSC in the NP and URPL groups showed different gene and pathway signature, including apoptosis. Apoptosis of decidual PMN-MDSC was mediated by TNF-related apoptosis–induced ligand (TRAIL) in a Caspase 3 dependent manner. TRAIL was expressed in decidua and upregulated in decidua of the URPL group. Notably, of all the membrane TRAIL receptors, only DcR2 was down-regulated in PMN-MDSC in the URPL group. In vitro experiment demonstrated that DcR2 blockade sensitized PMN-MDSC to TRAIL-mediated apoptosis. Together, these data indicate that increased TRAIL and reduced DcR2 on PMN-MDSC sensitize PMN-MDSC response to TRAIL-induced apoptosis in the URPL group, which is responsible for decreased accumulation of PMN-MDSC in URPL.
Highlights
Recurrent pregnancy loss (RPL), defined as two or more failed pregnancies, occurs in 5% pregnancies and about 50% of all RPL are idiopathic, which is defined as unexplained RPL (URPL) [1, 2]
PMN-myeloid-derived suppressor cells (MDSC) were defined as HLA-DR−/lowCD11b+CD33+CD15+CD14− and monocytic MDSC (M-MDSC) were defined as HLA-DR−/lowCD11b+CD33+CD15−CD14+ (Figure 1A)
We found that both CD33dimCD15+ polymorphonuclear MDSC (PMNMDSC) and CD33brightCD14+ M-MDSC existed in decidua of early pregnancy
Summary
Recurrent pregnancy loss (RPL), defined as two or more failed pregnancies, occurs in 5% pregnancies and about 50% of all RPL are idiopathic, which is defined as unexplained RPL (URPL) [1, 2]. Immune suppressive activity is the hallmark of MDSC. In different contexts MDSC suppress the immune response via different mechanisms [7]. MDSC are involved in the maintenance of immune tolerance of pregnancy by inhibiting cytotoxic T cells activation, suppressing NK cells killing activities and regulating regulatory T cells [5, 6, 13, 14]. Fetal-derived factor HLA-G plays a role in PMN-MDSC accumulation via STAT3 pathway stimulation [17]. Little is known about transcription features and cell fate of MDSC in normal pregnancy (NP) and URPL.
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