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Natural killer cells and pregnancy

Nature Reviews Immunology volume 2, pages 656–663 (2002)Cite this article

An Erratum to this article was published on 01 December 2002

Key Points

  • The main population of lymphoid cells in the mucosa of the uterus during early pregnancy are CD56bright natural killer (NK) cells. Their number decreases from mid-gestation onwards and they are absent at term.

  • Uterine NK (uNK) cells are influenced by sex hormones, particularly progesterone. There is recent evidence that endometrial-derived interleukin-15 and prolactin also affect their proliferation and differentiation.

  • All uNK cells express high levels of the inhibitory CD94/NKG2A receptor, the ligand for which is HLA-E. Killer-cell immunoglobulin-like receptors (KIRs) that are specific for HLA-C are also expressed by a higher proportion of uNK cells than by peripheral-blood NK cells in pregnant women, which indicates that the NK-cell receptor repertoire is skewed towards recognition of HLA-C in the uterus and could be induced by the local environment. Other receptors, such as KIR2DL4 and immunoglobulin-like transcript 2 (ILT2), the ligand for which is thought to be HLA-G, are also expressed by uNK cells.

  • As HLA-C, HLA-E and HLA-G are expressed by the population of extravillous trophoblast (EVT) cells that invades the uterus, it has been proposed that interaction between these trophoblast MHC class I molecules and uNK-cell receptors could be important for the control of implantation.

  • HLA-E would be expected to be the overall inhibitory ligand through interaction with CD94/NKG2A. Interestingly, the presence of a peptide that is derived from the leader sequence of HLA-G can influence the binding of HLA-E to its receptor. As HLA-G is expressed only by EVT, this is one way in which trophoblast can specifically influence uNK-cell activity.

  • HLA-C is the only one of the three trophoblast MHC class I molecules that is polymorphic. As all women express KIRs for both groups of HLA-C alleles, the recognition of paternal non-self HLA-C should occur during pregnancy. It is possible that some combinations of paternal HLA-C and maternal KIRs are sub-optimal for implantation, leading to diseases such as pre-eclampsia, for which partner specificity, and correlation with first pregnancy and oocyte donation are characteristic features of an immunological pathogenesis.

  • Although the interaction between trophoblast class I molecules and uNK cells is likely to provide the pivotal control for successful implantation, it is unclear how it is mediated. Uterine NK cells might have a dual role to play in reproduction, by monitoring mucosal integrity throughout the menstrual cycle and controlling trophoblast invasion during pregnancy.

  • The extraordinary species diversity in the anatomy of placentation has made direct comparison between humans and animals difficult. Nevertheless, much can be deduced from animal studies. Uterine NK cells from different species might have evolved different mechanisms to support successful reproduction.

  • The fetus and placenta have traditionally been considered to be analogous to an allograft. However, it is the evolutionarily older innate immune system that seems to have a dominant influence on reproduction. Conceptually, this is an important paradigm shift and offers a new insight into the immunology of reproduction.

Abstract

The fetus is considered to be an allograft that, paradoxically, survives pregnancy despite the laws of classical transplantation immunology. There is no direct contact of the mother with the embryo, only with the extraembryonic placenta as it implants in the uterus. No convincing evidence of uterine maternal T-cell recognition of placental trophoblast cells has been found, but instead, there might be maternal allorecognition mediated by uterine natural killer cells that recognize unusual fetal trophoblast MHC ligands.

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Figure 1: Anatomy of the trophoblast populations that are present at the fetal–maternal boundary in the first trimester of pregnancy.
Figure 2: The blood flow through the maternal uterine arteries is increased by the infiltration of the arterial media and endothelium by extravillous trophoblast cells.

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Acknowledgements

I am grateful to Y. W. Loke for comments on the manuscript and to J. Connor for secretarial help. Research in my laboratory is supported by the Wellcome Trust, the National Institutes of Health, the British Heart Foundation and the Isaac Newton Trust.

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  1. Department of Pathology, Cambridge University, Tennis Court Road, Cambridge, CB2 1QP, UK

    Ashley Moffett-King

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DATABASES

LocusLink

ANG2

β2-microglobulin

CD1D

CD66

CD94

CSF1

GM-CSF

HLA-C

HLA-E

HLA-G

IFN-α

IFN-β

IFN-γ

IL-2

IL-15

ILT2

ILT4

KIR2DL4

LIF

Ly49

MICA

MICB

NKG2

NKG2A

NKG2C

PIGF

prolactin

TNF

ULBP

VCAM1

VEGFC

Glossary

VIVIPARITY

The bearing of live young who derive nutrition directly from the mother.

VILLOUS TROPHOBLAST

The trophoblast cells that cover the placental villi, which project into the intervillous space that is perfused with maternal blood.

PRE-ECLAMPSIA

A disease that is specific to pregnancy that is caused by the presence of the placenta. It is characterized by diverse systemic symptoms that are triggered by endothelial dysfunction, which commonly include hypertension and proteinuria. The incidence varies from 3–10% of pregnancies, and this disease is the leading cause of maternal mortality and fetal morbidity and mortality throughout the world.

CORPUS LUTEUM

An endocrine gland that produces both oestrogen and progesterone, which is formed from the wall of the Graafian follicle after ovulation has occurred.

ONCOFETAL ANTIGENS

Antigens that are normally expressed only during early development, but that are re-expressed by malignant cells in adults.

TETRAMER

A soluble reagent that consists of a fluorophore-conjugated core surrounded by four peptide–MHC complexes.

HAEMOCHORIAL

A form of placentation in which trophoblast cells erode the maternal vasculature, which results in the direct contact of maternal blood with trophoblast.

STAMPER WOODRUFF ASSAY

An assay in which the adherence of lymphocytes to tissue-specific endothelial cells is studied using tissue sections.

VASCULAR ADRESSINS

Adhesion molecules that are differentially expressed on endothelial cells in various anatomical locations; they bind to cognate ligands on leukocyte subsets and direct their homing to specific microenvironments.

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Moffett-King, A. Natural killer cells and pregnancy. Nat Rev Immunol 2, 656–663 (2002). https://doi.org/10.1038/nri886

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