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

子宫自然杀伤细胞 (uNK) 上的 KIR 如何调节人类妊娠成功？

• 批准号: MR/P001092/1
• 负责人: Andrew Sharkey
• 金额: $ 70.15万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP001092%2F1
• 关键词: How; do; KIR; uterine; Natural

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.

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造成的。在怀孕早期，胎盘中的胎儿细胞（称为滋养层细胞）会侵入子宫并利用子宫的血液供应来维持胎儿的生长。这一过程失败会导致胎盘血液供应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症（先兆子痫），其特点是孕妇血压高，并可能损害肾脏和其他器官。我们正在研究子宫内膜中的母体免疫细胞（称为子宫自然杀伤（uNK）细胞）如何调节滋养层侵袭的程度。 uNK 细胞具有称为 KIR 的受体，它像锁和钥匙一样与来自胎盘的入侵滋养层细胞上的 HLA 分子结合。锁和钥匙都可能有所不同。我们的遗传学研究表明，当某些 KIR 受体（仅存在于某些母亲中）与滋养层 HLA 结合时，会导致胎盘发育异常，并增加先兆子痫或小婴儿的风险。然而，其他 KIR 受体与 HLA 的结合不会导致这个问题。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层细胞上的HLA分子时，母体的NK细胞会如何反应？我们还想问为什么某些类型的 KIR 引发的反应有害，而另一些则促进胎盘发育？我们将识别 uNK 细胞的“有益”和“有害”反应，并研究它们如何影响滋养层侵袭。了解 uNK 的不同反应将有助于我们确定哪些怀孕风险最大，如果我们要开发治疗这些常见妊娠疾病的方法，这是至关重要的第一步。 NK 细胞（如子宫中的 NK 细胞）存在于体内的许多组织中，但在器官之间表现出显着差异。与血液中的 NK 细胞相比，这些“组织 NK 细胞”的研究很少。此外，即使在同一组织内，NK 细胞的反应也表现出巨大的差异。这将是对组织 NK 细胞的首批研究之一，使用的技术可以了解组织中许多不同类型 NK 细胞的反应是如何被控制的。我们的研究结果将产生更广泛的影响，因为针对组织 NK 细胞的治疗干预措施正在开发中，用于治疗包括癌症和移植在内的一系列疾病。

项目成果

Tissue stiffness at the human maternal-fetal interface

人类母胎界面的组织硬度

• DOI: 10.17863/cam.41558
• 发表时间: 2019
• 作者: Abbas Y

Isolation of Uterine Innate Lymphoid Cells for Analysis by Flow Cytometry.

分离子宫先天淋巴细胞用于流式细胞术分析。

• DOI: 10.3791/62670
• 发表时间: 2021
• 期刊: JoVE
• 作者: Depierreux DM

Beyond Maternal Tolerance: Education of Uterine Natural Killer Cells by Maternal MHC Drives Fetal Growth.

• DOI: 10.3389/fimmu.2022.808227
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Fetal Medicine, 3rd Edition

胎儿医学，第三版

• 发表时间: 2019
• 作者: Ashley Moffett

Education of uterine natural killer cells by maternal MHC drives fetal growth

母体 MHC 对子宫自然杀伤细胞的教育促进胎儿生长

• DOI: 10.4049/jimmunol.208.supp.59.13
• 发表时间: 2022
• 期刊: The Journal of Immunology
• 作者: Depierreux D