Abstract

BACKGROUND

Recurrent miscarriage and pre-eclampsia are common reproductive disorders, but their causes are often unknown. Recent evidence has provided new insight into immune system influences in reproductive disorders. A subset of lymphocytes of the innate immune system known as uterine natural killer (uNK) cells are now recognized as fundamental to achieving embryo implantation and successful pregnancy, but were initially attributed a bad reputation. Indeed, immune therapies have been developed to treat the ‘exaggerated’ immune response from uNK cells. These treatments have been based on studies of peripheral blood natural killer (pbNK) cells. However, uNK cells and pbNK cells have different phenotypic and functional characteristics. The functions of uNK cells are closely related to their interactions with the extravillous trophoblast cells (EVTs) and spiral arteries, which underlie an essential role in regulating vascular function, controlling trophoblast invasion and promoting placental development. EVTs express MHC molecules of class I HLA-C/E/G/F, while uNK cells express, among other receptors, killer cell immunoglobulin-like receptors (KIRs) that bind to HLA-C or CD94/NKG2A inhibitory receptors, and then bind HLA-E. Associations of certain KIR/HLA-C combinations with recurrent miscarriage, pre-eclampsia, and foetal growth restriction and the interactions between uNK cells, trophoblasts and vascular cells have led to the hypothesis that uNK cells may play a role in embryo implantation.

OBJECTIVE AND RATIONALE

Our objective was to review the evolution of our understanding of uNK cells, their functions, and their increasingly relevant role in reproduction.

SEARCH METHODS

Relevant literature through June 2020 was retrieved using Google Scholar and PubMed. Search terms comprised uNK cells, human pregnancy, reproductive failure, maternal KIR and HLA-C, HLA-E/G/F in EVT cells, angiogenic cytokines, CD56⁺ NK cells, spiral artery, oestrogen and progesterone receptors, KIR haplotype and paternal HLA-C2.

OUTCOMES

This review provides key insights into the evolving conceptualization of uNK cells, from their not-so-promising beginnings to now, when they are considered allies in reproduction. We synthesized current knowledge about uNK cells, their involvement in reproduction and their main functions in placental vascular remodeling and trophoblast invasion. One of the issues that this review presents is the enormous complexity involved in studying the immune system in reproduction. The complexity in the immunology of the maternal–foetal interface lies in the great variety of participating molecules, the processes and interactions that occur at different levels (molecular, cellular, tissue, etc.) and the great diversity of genetic combinations that are translated into different types of responses.

WIDER IMPLICATIONS

Insights into uNK cells could offer an important breakthrough for ART outcomes, since each patient could be assessed based on the combination of HLA and its receptors in their uNK cells, evaluating the critical interactions at the materno–foetal interface. However, owing to the technical challenges in studying uNK cells in vivo, there is still much knowledge to gain, particularly regarding their exact origin and functions. New studies using novel molecular and genetic approaches can facilitate the identification of mechanisms by which uNK cells interact with other cells at the materno–foetal interface, perhaps translating this knowledge into clinical applicability.

中文翻译：

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子宫自然杀伤细胞：在繁殖过程中从敌人到朋友

摘要

背景

反复流产和先兆子痫是常见的生殖系统疾病，但其原因往往未知。最近的证据为免疫系统对生殖疾病的影响提供了新的见解。被称为子宫自然杀伤 (uNK) 细胞的先天免疫系统淋巴细胞子集现在被认为是实现胚胎植入和成功怀孕的基础，但最初被认为是一个坏名声。事实上，已经开发出免疫疗法来治疗来自 uNK 细胞的“过度”免疫反应。这些治疗基于对外周血自然杀伤 (pbNK) 细胞的研究。然而，uNK 细胞和 pbNK 细胞具有不同的表型和功能特征。uNK细胞的功能与其与绒毛外滋养层细胞（EVTs）和螺旋动脉的相互作用密切相关，它们在调节血管功能、控制滋养层侵袭和促进胎盘发育方面发挥着重要作用。EVT 表达 I 类 HLA-C/E/G/F 的 MHC 分子，而 uNK 细胞表达与 HLA-C 或 CD94/NKG2A 抑制受体结合的杀伤细胞免疫球蛋白样受体 (KIR) 等受体，然后结合 HLA-E。某些 KIR/HLA-C 组合与复发性流产、先兆子痫和胎儿生长受限的关联以及 uNK 细胞、滋养层和血管细胞之间的相互作用导致了 uNK 细胞可能在胚胎植入中发挥作用的假设。控制滋养层的侵袭，促进胎盘发育。EVT 表达 I 类 HLA-C/E/G/F 的 MHC 分子，而 uNK 细胞表达与 HLA-C 或 CD94/NKG2A 抑制受体结合的杀伤细胞免疫球蛋白样受体 (KIR) 等受体，然后结合 HLA-E。某些 KIR/HLA-C 组合与复发性流产、先兆子痫和胎儿生长受限的关联以及 uNK 细胞、滋养层和血管细胞之间的相互作用导致了 uNK 细胞可能在胚胎植入中发挥作用的假设。控制滋养层的侵袭，促进胎盘发育。EVT 表达 I 类 HLA-C/E/G/F 的 MHC 分子，而 uNK 细胞表达与 HLA-C 或 CD94/NKG2A 抑制受体结合的杀伤细胞免疫球蛋白样受体 (KIR) 等受体，然后结合 HLA-E。某些 KIR/HLA-C 组合与复发性流产、先兆子痫和胎儿生长受限的关联以及 uNK 细胞、滋养层和血管细胞之间的相互作用导致了 uNK 细胞可能在胚胎植入中发挥作用的假设。

目标和理由

我们的目标是回顾我们对 uNK 细胞、它们的功能以及它们在繁殖中日益重要的作用的理解的演变。

搜索方法

使用Google Scholar和PubMed检索到 2020 年 6 月的相关文献。搜索词包括 uNK 细胞、人类妊娠、生殖失败、母体 KIR 和 HLA-C、EVT 细胞中的 HLA-E/G/F、血管生成细胞因子、CD56 ⁺ NK 细胞、螺旋动脉、雌激素和孕激素受体、KIR 单倍型和父系HLA-C2。

结果

这篇综述提供了关于 uNK 细胞不断发展的概念化的关键见解，从它们不太有希望的开始到现在，当它们被认为是繁殖的盟友时。我们综合了有关 uNK 细胞、它们参与繁殖及其在胎盘血管重塑和滋养层侵袭中的主要功能的当前知识。这篇综述提出的问题之一是研究生殖免疫系统所涉及的巨大复杂性。母胎界面免疫学的复杂性在于参与的分子种类繁多，发生在不同水平（分子、细胞、组织等）的过程和相互作用以及转化为的遗传组合的多样性。不同类型的响应。

更广泛的影响

对 uNK 细胞的了解可以为 ART 结果提供重要突破，因为可以根据 HLA 及其 uNK 细胞中的受体的组合对每个患者进行评估，评估母胎界面的关键相互作用。然而，由于在体内研究 uNK 细胞的技术挑战，仍然有很多知识需要获得，特别是关于它们的确切来源和功能。使用新的分子和遗传方法的新研究可以促进识别 uNK 细胞与母胎界面上的其他细胞相互作用的机制，或许将这些知识转化为临床适用性。