How do KIR on uterine Natural Killer cells (uNK) regulate human pregnancy success?

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Several major disorders that women face during pregnancy, result from failure of the placenta to implant correctly into the mother's uterus or womb. During early pregnancy, fetal cells from the placenta, known as trophoblast cells, invade into the uterus and tap into her blood supply to sustain the growing baby. Failure of this process can lead to insufficient blood supply to the placenta and low birth weight babies. The 'starved' placenta can also cause a life-threatening syndrome (pre-eclampsia), which is characterised by a high maternal blood pressure and possible damage to her kidneys and other organs.We are investigating how maternal immune cells in the lining of the uterus, known as uterine Natural Killer (uNK) cells, regulate the extent of trophoblast invasion. uNK cells have receptors called KIR that bind like a lock and key to HLA molecules on the invading trophoblast cells from the placenta. Both lock and key can vary. Our genetic studies show that when certain KIR receptors (present only in some mothers) bind to trophoblast HLA, this causes abnormal placental development and increases the risk of pre-eclampsia or a small baby. However binding of other KIR receptors to HLA does not cause this problem. Our question is: how do the mother's NK cells respond when these two different types of KIR recognise and bind the HLA molecules on the fetal trophoblast cells? We also want to ask why are responses triggered by some types of KIR detrimental while others enhance placental development? We will identify 'beneficial' and 'detrimental' responses by uNK cells and examine how they affect trophoblast invasion. Understanding the different responses of uNK will help us to pinpoint which pregnancies are at greatest risk and is an essential first step if we are to develop ways to treat these common disorders of pregnancy. NK cells like those in the uterus are found in many tissues in the body, but show significant differences between organs. These 'tissue NK cells' have been very little studied compared with NK cells in blood. Also, NK cells even within the same tissue show tremendous variation in their responses. This will be one of the first studies of tissue NK cells, using techniques that can see how the responses of the many different types of NK cells in the tissue are controlled. Our findings will have wider implications, since therapeutic interventions targeting tissue NK cells are being developed for a range of diseases including cancer and in transplantation.