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

妇女在怀孕期间面临的几种主要疾病是由于胎盘未能正确植入母亲的子宫或子宫所致。在怀孕早期，来自胎盘的胎儿细胞，被称为滋养细胞，侵入子宫，利用她的血液供应来维持婴儿的生长。这一过程的失败会导致胎盘供血不足和低出生体重婴儿。“饥饿”的胎盘还会导致危及生命的综合征（先兆子痫），其特征是孕妇血压高，并可能损害其肾脏和其他器官。我们正在研究子宫内膜的母体免疫细胞，即子宫自然杀伤细胞（uNK）如何调节滋养细胞侵袭的程度。uNK细胞有一种叫做KIR的受体，它像锁和钥匙一样与来自胎盘的入侵滋养细胞上的HLA分子结合。锁和钥匙都可以变化。我们的遗传学研究表明，当某些KIR受体（仅存在于一些母亲）与滋养细胞HLA结合时，会导致胎盘发育异常，增加先兆子痫或小婴儿的风险。然而，其他KIR受体与HLA结合不会引起这个问题。我们的问题是：当这两种不同类型的KIR识别并结合胎儿滋养细胞上的HLA分子时，母亲的NK细胞是如何反应的？我们还想问，为什么某些类型的KIR引发的反应是有害的，而另一些则促进了胎盘的发育？我们将确定uNK细胞的“有益”和“有害”反应，并研究它们如何影响滋养细胞的侵袭。了解uNK的不同反应将帮助我们确定哪些妊娠风险最大，如果我们要找到治疗这些常见妊娠疾病的方法，这是必不可少的第一步。像子宫一样的NK细胞存在于身体的许多组织中，但在器官之间表现出明显的差异。与血液中的NK细胞相比，对这些“组织NK细胞”的研究很少。此外，即使在同一组织内的NK细胞也表现出巨大的反应差异。这将是对组织NK细胞的首次研究之一，使用的技术可以看到组织中许多不同类型NK细胞的反应是如何被控制的。我们的发现将具有更广泛的意义，因为针对组织NK细胞的治疗干预措施正在开发用于包括癌症和移植在内的一系列疾病。

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.