Abstract
Unexplained recurrent spontaneous abortion (URSA) is believed to be associated with impaired immunosuppression at the maternal-fetal interface, but the detailed molecular mechanism remains unclear. The ATP-adenosine metabolic pathway regulated by CD39/CD73 has recently been recognized to be important in immunosuppression. This study aimed to investigate the regulation of decidual natural killer (dNK) cells and fetal extravillous trophoblast (EVT) cells by CD39 and CD73 in URSA, as well as the possible regulatory mechanism of CD39/CD73 via the TGF-β-mTOR-HIF-1α pathway using clinical samples and cell models. Fewer CD39+ and CD73+ cells were found in the URSA decidual and villous tissue, respectively. Inhibition of CD39 on dNK cells transformed the cells to an activated state with increased toxicity and decreased apoptosis, and changed their cytokine secretion, leading to impaired invasion and proliferation of the co-cultured HTR8/SVneo cells. Similarly, inhibition of CD73 on HTR8/SVneo cells decreased the adenosine concentration in the cell culture media, increased the proportion of CD107a+ dNK cells, and decreased the invasion and proliferation capabilities of the HTR8/SVneo cells. In addition, transforming growth factor-β (TGF-β) triggered phosphorylation of mammalian target of rapamycin (mTOR) and Smad2/Smad3, which subsequently activated hypoxia-inducible factor-1α (HIF-1α) to induce the CD73 expression on the HTR8/SVneo cells. In summary, reduced numbers of CD39+ and CD73+ cells at the maternal-fetal interface, which may be due to downregulated TGF-β-mTOR-HIF-1α pathway, results in reduced ATP-adenosine metabolism and increased dNK cytotoxicity, and potentially contributes to URSA occurrences.
Highlights
Unexplained recurrent spontaneous abortion (URSA) is defined as two or more consecutive spontaneous abortions [1, 2]
It was found that CD39 was present in the Decidual natural killer (dNK) cells that express CD56, and CD73 was present in trophoblast cells that express CK7 (Figures 1A and S2)
Since there are multiple types of immune cells in the decidual tissue expressing CD39, we further used multicolor flow cytometry to measure the proportions of CD39+ dNK cells in the decidua of normal pregnancies and URSA patients
Summary
Unexplained recurrent spontaneous abortion (URSA) is defined as two or more consecutive spontaneous abortions [1, 2]. Natural killer (NK) cells, a population of innate lymphoid cells, can lyse cancer cells and virus-infected cells. They play an important role in controlling the adaptive immune response by producing pro-inflammatory and anti-inflammatory cytokines [5, 6]. The dNK cells express a variety of surface receptors, such as NKp44 (CD336), NKp30 (CD337) and NKG2D (CD314) [1, 2] When these receptors are activated, an array of cytokines and growth factors that regulate the immune tolerance and angiogenesis at the maternal-fetal interface are produced, including GM-CSF, TNF-a, IFN-g, IL-10, IL-8, IL-2, interferon-inducible protein-10 (IP-10), hepatocyte growth factor (HGF), PLGF, CCL-3, CCL-4 and several vascular endothelial growth factor (VEGF) family members [2, 9]
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