Our goal is to understand how the uterine immune system regulates placentation and reproductive success in humans and to use this knowledge to develop improved procedures for predicting and dealing with disorders of pregnancy. The placenta is the critical interface between the mother and her fetus. It regulates the delivery of oxygen and nutrients to the fetus. Normal fetal growth and development depend on the crucial period early in pregnancy when placental trophoblast cells drive into the maternal uterine arteries to open up the blood supply. Clinically, disorders of placentation are manifest in a diverse range of conditions including pre-eclampsia, stillbirth, fetal growth restriction and preterm labour, as well as the long-term consequences of under-nutrition in utero on adult health. It is these disorders and their biological bases that are the focus of our research proposal. We have shown that the proper delineation of the maternal-fetal boundary, and thus the depth of placentation, is regulated by a novel mechanism of maternal allogeneic recognition that depends on KIR, a set of variable immunoreceptors (including both inhibitory and activating variants) expressed by uterine NK (uNK) cells and their ligands, HLA-C, on fetal trophoblast. KIR and HLA-C genes are highly polymorphic and we find that reproducible and specific maternal KIR/fetal HLA-C combinations are associated with reproductive disorders. Understanding the functional consequences of the interaction between specific KIR and HLA-C variants is a fundamental aspect of our proposal and is intended to show how the detailed biology of placental invasion translates into clinical consequences in normal and abnormal pregnancies.