Review
Do uterine natural killer (uNK) cells contribute to female reproductive disorders?

https://doi.org/10.1016/j.jri.2011.01.003Get rights and content

Abstract

The most abundant immune cells in the uterine decidua around the time of implantation and early placental development are the uterine natural killer (uNK) cells. Altered numbers of uNK cells have been associated with several human reproductive disorders, including recurrent miscarriage, recurrent implantation failure, uterine fibroids, sporadic miscarriage, fetal growth restriction and preeclampsia. Understanding of the function of uNK cells in non-pregnant and pregnant endometrium is now increasing; the potential contribution of altered numbers and function of uNK cells to reproductive disorders is the focus of this review.

Introduction

Immune cells are a key feature of non-pregnant endometrium and decidualised endometrium in pregnancy. One such immune cell type is the uterine natural killer (uNK) cells, altered numbers of which have been associated with recurrent miscarriage (Quenby et al., 1999), recurrent implantation failure (Tuckerman et al., 2010), uterine leiomyomata (fibroids) (Kitaya and Yasuo, 2010), sporadic miscarriage (Zenclussen et al., 2001), fetal growth restriction (Williams et al., 2009a) and preeclampsia (Williams et al., 2009a). Understanding of the function of these cells in non-pregnant and pregnant endometrium is now increasing and clarification of the potential contribution of altered numbers and function of uNK cells to reproductive disorders may therefore now be possible.

Section snippets

Uterine natural killer cells

Uterine NK cells are the most abundant of all decidual leucocytes accounting for up to approximately 70% of decidual stromal CD45+ cells in the first trimester of human pregnancy. Uterine NK cells are brightly CD56-positive but are CD16-negative; they therefore differ phenotypically from ‘usual’ peripheral blood NK cells which are CD56+CD16+. Although a small population of CD56brightCD16 NK cells are detectable in peripheral blood, these are usually agranular; in contrast uNK cells are CD56

Distribution of uNK cells in non-pregnant and pregnant uterine endometrium

Initially uNK cells were identified by the presence of phloxinophilic cytoplasmic granules using the phloxine tartrazine histochemical stain. They were reported to be absent in proliferative endometrium, with numbers increasing in the mid and late secretory phase of the menstrual cycle and in pregnancy until the third month of gestation; thereafter they were reported to decline to be virtually absent at term (Hamperl and Hellweg, 1958, Dallenbach-Hellweg and Nette, 1964). This distribution was

Functional investigations

The precise in vivo functions of uNK cells are still not clear. However, in vitro studies are providing clues to their functions in early human pregnancy, although further studies are required to determine the function of uNK cells in non-pregnant endometrium.

Uterine NK cells in reproductive disorders

Altered numbers of uNK cells have been detected in the endometrium and in early pregnancy decidua from women with various reproductive disorders including recurrent miscarriage, recurrent implantation failure, uterine leiomyomata (fibroids), sporadic miscarriage, fetal growth restriction and preeclampsia.

Conclusions

Uterine natural killer cells are the most abundant leucocyte in mid and late secretory phase non-pregnant endometrium and early pregnancy decidua. Diverse roles have been proposed ranging from immune function, cytokine and growth factor secretion, regulation of trophoblast invasion and regulation of the initial stages of spiral artery remodelling. Altered numbers of uNK cells have been associated with several different reproductive disorders and given their known functions a causative role in

Acknowledgements

Research in the laboratory of JNB and GEL has been funded by BBSRC, Wellbeing of Women and The Royal Society.

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      Compared to pNK cells, uNK are less cytotoxic and have a different profile of secreted cytokines and receptor/gene expression, while both pNK and uNK cells possess immunomodulatory functions (Tang et al., 2011; Seshadri and Sunkara, 2014). UNK cells play an important role in trophoblast invasion and angiogenesis and represent about 70 % of immune cells at the feto-maternal interface (Lash and Bulmer, 2011). Elevations of uNK cells have been associated with hypertensive pregnancy disorders, preeclampsia and fetal growth restriction (Lyall et al., 2013; Koo et al., 2015; Hashemi et al., 2017).

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