Fundación IVI, Innovation-IIS La Fe, Valencia 46026, Spain.
Department of Immunology and Department of Reproductive Endocrinology and Infertility, Instituto Valenciano de Infertilidad-Madrid, Rey Juan Carlos University (IVI), Madrid 28023, Spain.
Hum Reprod Update. 2021 Jun 22;27(4):720-746. doi: 10.1093/humupd/dmaa062.
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.
Our objective was to review the evolution of our understanding of uNK cells, their functions, and their increasingly relevant role in reproduction.
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.
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.
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.
复发性流产和子痫前期是常见的生殖系统疾病，但病因通常不明确。最近的证据为免疫系统在生殖系统疾病中的作用提供了新的见解。先天免疫系统中的淋巴细胞亚群之一，即子宫自然杀伤 (uNK) 细胞，被认为是胚胎着床和成功妊娠的基础，但最初被认为是有害的。事实上，已经开发出免疫疗法来治疗 uNK 细胞的“过度”免疫反应。这些治疗方法是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 (EVT) 和螺旋动脉的相互作用密切相关，这对于调节血管功能、控制滋养细胞浸润和促进胎盘发育至关重要。EVT 表达 HLA-C/E/G/F 类别的 MHC 分子，而 uNK 细胞表达杀伤细胞免疫球蛋白样受体 (KIR) 等其他受体，这些受体与 HLA-C 或 CD94/NKG2A 抑制性受体结合，然后与 HLA-E 结合。某些 KIR/HLA-C 组合与复发性流产、子痫前期和胎儿生长受限的关联，以及 uNK 细胞、滋养层细胞和血管细胞之间的相互作用，导致了 uNK 细胞可能在胚胎着床中发挥作用的假说。
我们的目的是回顾我们对 uNK 细胞的理解的演变，以及它们的功能及其在生殖中的日益相关的作用。
使用 Google Scholar 和 PubMed 检索了截至 2020 年 6 月的相关文献。检索词包括 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。
这篇综述提供了对 uNK 细胞不断发展的概念的重要见解，从它们不太乐观的开始到现在，它们被认为是生殖的盟友。我们综合了当前关于 uNK 细胞的知识，包括它们在生殖中的作用及其在胎盘血管重塑和滋养层浸润中的主要功能。本综述提出的一个问题是，研究生殖系统免疫系统的复杂性极大。母体-胎儿界面免疫的复杂性在于参与的分子种类繁多，在不同水平（分子、细胞、组织等）发生的过程和相互作用，以及转化为不同类型反应的遗传组合的多样性。
对 uNK 细胞的深入了解可能为辅助生殖技术的结果提供重要突破，因为可以根据患者 uNK 细胞中的 HLA 及其受体的组合对每位患者进行评估，评估母体-胎儿界面的关键相互作用。然而，由于在体内研究 uNK 细胞存在技术挑战，因此仍有很多知识需要了解，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 细胞与母体-胎儿界面上其他细胞相互作用的机制，也许可以将这些知识转化为临床适用性。
