Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Summary Fetal growth and development during human pregnancy depends on delivery of adequate maternal oxygen and nutrients to the fetus via the placenta. In humans, the balanced invasion of fetal placental trophoblast cells into the maternal uterine lining, where they interact with uterine natural killer cells (uNK), is thought to be critical for a successful pregnancy but exactly how this influences reproductive outcomes remains undefined. Here, we used our trophoblast organoid model and primary tissue samples to determine how uNK affect placentation. By locating potential interaction axes between primary trophoblast cells and uNK using single cell transcriptomics, and in vitro modelling of these interactions in trophoblast organoids, we identify a uNK-derived cytokine signal that promotes trophoblast differentiation by enhancing epithelial-mesenchymal transition and increasing trophoblast cells at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in increasing blood flow, placental access to nutrients, and dampening inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings shed new light on how optimal immunological interactions between maternal uNK cells and fetal trophoblast enhance reproductive success.