SAHA modulates MICA and ULBPs expression on JEG-3 cells and enhances their susceptibility to NK cell-mediated cytotoxicity

Pregnancy is characterized by the emergence of a unique immunotolerant microenvironment that supports fetal development. Trophoblast cells and natural killer (NK) cells cooperate to establish the microenvironment essential for successful embryo implantation. Potential participants in this process include the activating NK cell receptor NKG2D and its ligands (NKG2D-Ls): MICA, MICB (MIC), and the family of UL16-binding proteins (ULBPs 1-6). The mentioned ligands may enhance the cytotoxic activity of lymphocytes. There is also a mechanism that involves the secretion of soluble NKG2D-L (sMIC, sULBPs). This feature allows NKG2D-L-expressing cells to evade immune recognition and, in general, suppress the functional activity of NK cells. To date, the contribution of NKG2D-L molecules to interactions between placental and immune cells remains poorly studied. Currently, it is not clear which specific placental cell types are the primary producers of MIC molecules, with trophoblast cells representing the likely candidates. These cells express a wide spectrum of ligands specific to NK-cell receptors, and their interaction facilitates the implantation process. The expression levels of genes encoding NKG2D-L may be changed, depending on the microenvironmental conditions. Expression of NKG2D-L is regulated by external factors, including histone deacetylase inhibitors (HDACi). In the present study, we aimed to investigate the effect of suberoylanilide hydroxamic acid (SAHA) on NKG2D-L expression in trophoblast cells and to evaluate changes in NK cells following their interaction with SAHA-treated trophoblast cells. We have shown that SAHA may modulate NKG2D-Ls expression on trophoblast cells in a dose-dependent manner. At high concentrations, SAHA increased the proportion of MICA-expressing trophoblast cells, whereas low concentrations resulted in reduced expression intensity of ULBP2, ULBP5, and ULBP6. Co-culture with NK cells also altered trophoblast expression of MICA and ULBP molecules; however, this effect was abrogated at higher SAHA concentrations. Notably, high-dose SAHA treatment enhanced trophoblast susceptibility to NK cell-mediated cytotoxicity, which correlated with an increased frequency of MICA-positive trophoblast cells. These findings indicate that the NKG2D-NKG2D-L interaction represents a potential regulatory axis in modulating trophoblast–NK cell crosstalk during pregnancy.