Differences in the Expression of KIR, ILT Inhibitory Receptors, and VEGF Production in the Induced Decidual NK Cell Cultures of Fertile and RPL Women

Abstract

Problem. Natural killer (NK) cells are the most abundant leukocyte population in the uterus. The interactions of the maternal NK expression of killer cell immunoglobulin-like receptors (KIRs) and human inhibitory receptor Ig-like transcript (ILT) with fetal HLA determine the activation of NK cells and pregnancy outcomes. Moreover, dNK cells release numerous angiogenic factors including VEGF. Our previous study showed that sildenafil citrate (SC) significantly decreased peripheral blood NK (pbNK) cell activity and improved intrauterine blood flow, which correlated with a successful pregnancy outcome. Thus, in this study, we investigated whether SC influenced the expression of KIR or ILT receptors on induced decidual NK (idNK), the apoptosis of cells, and VEGF-A production in the culture supernatants of idNK cells. Method of Study. pbNK cells from 24 healthy women and 23 women with RPL were converted to idNK cells under hypoxia, IL-15, and TGF-β conditions. The cultures were prepared with or without SC. Changes in KIR2DL1 (CD158a), NKG2A (CD159a), ILT-2 (CD85j), and ILT-4 (CD85d) expression on CD56+CD16- cells and their apoptosis were determined via flow cytometry. VEGF-A level was established in culture supernatants with the ELISA method. Results. KIR2DL1 and ILT-2 expression on idNK cells was higher in healthy women than in RPL patients. Sildenafil enhanced NKG2A expression in RPL patients. VEGF concentration was higher in fertile woman idNK cell cultures. idNK cells were more sensitive for necrosis in RPL than in fertile women. SC did not influence VEGF production or idNK cell apoptosis. Conclusions. A combination of hypoxia, IL-15, and AZA promotes the conversion of pbNK into idNK cells CD56+CD16--expressing KIR receptors and produces VEGF. Alterations in KIR2DL1 and ILT-2 expression as well as impaired VEGF production were associated with RPL. SC affects NKG2A expression on RPL idNK cells. SC had no effect on VEGF release or idNK cell apoptosis.

Natural killer cell-mediated immunopathology in recurrent pregnancy losses

“…When pNK cells from RPL were converted to induced dNK cells under hypoxia, IL-15, and TGF-β conditions, KIR2DL1 and Ig-like transcript 2 (ILT-2) expression on induced dNK cells were lower in women with RPL than in healthy controls. In addition, induced dNK cells from RPL were more sensitive to necrosis and produced a lower amount of VEGF than controls [140].…”

The predictive value of NKG2C+NK cells and LILRB1+NK cells in recurrent spontaneous abortion

“…Trophoblast and decidual stromal cell at maternal‐fetal interface could secret cytokines and chemokine and therefore inducing immune tolerance microenvironment 38 . It is widely recognized that pNK are recruited to decidua in response to chemokine and educated by decidual microenvironment to promote immunotolerance.…”

The Progress of Research on Genetic Factors of Recurrent Pregnancy Loss

“…Te generation of placental villi and embryonic vasculature is a critical step throughout embryonic development and is the foremost condition for embryo implantation. Te major inducers of angiogenesis are essential for stimulating trophoblast proliferation, embryonic vascular development, and the growth of maternal and fetal blood cells during early pregnancy [17]. Vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) are possible regulatory factors associated with RPL.…”