The associations of natural killer cell functions during the embryo implantation window with pregnancy outcomes in women for whom the number of peripheral blood natural killer cells cannot be applied as a therapeutic index for immunological abnormalities in unexplained recurrent pregnancy loss

Abstract Study objective The current knowledge on recurrent pregnancy loss (RPL) is largely limited, with up to 70% of RPL cases still classified as unexplained. More than 30% of patients with unexplained recurrent pregnancy loss (uRPL) will suffer an additional pregnancy loss. The majority of scholars are supportive of an immune basis, while clinical data fail to support established therapies. In addition, the effectiveness of immunotherapies is difficult to evaluate because of the lack of diagnostic and predictive indicators. Natural Killer (NK) cells are the largest population of lymphocytes in the endometrium during early pregnancy and play a key regulatory rather than participatory role in the cytotoxic killing reaction to embryos at the maternal-fetal interface. Specifically, they support the invasion of trophoblast cells and embryo implantation. Previous studies on the roles of NK cells with distinct phenotypes in pregnancy loss were based on NK cells derived from the peripheral blood or decidua, and it is difficult to determine whether the reported changes in decidual NK cells are causes or consequences of pregnancy loss. Hence, whether the results of these studies are applicable to the interaction between NK cells and embryonic trophoblast cells during the earliest pregnancy stage remains unknown. Design This study evaluated the expression of 9 receptors and cytokines after coculture of the HTR-8/SVneo human chorionic trophoblast cell line with peripheral blood NK (pbNK) cells and uterine NK (uNK) cells collected during the same embryo implantation window. Then the phenotypes of NK cells during this period were analyzed, and the associations of NK cell functional features with early pregnancy outcomes were explored. Results We found that a decrease in the CD3-CD56 + CD27 + uNK cell population and increases in the frequencies of CD3-CD56 + CD107a + NK cells in women with the recurrence of pregnancy loss. Conclusions CD3-CD56 + IFN-γ + pbNK cells and CD3-CD56 + IFN-γ + uNK cells were immunological risk factors associated with the recurrence of pregnancy loss in uRPL.