Uterine natural killer cells make up approximately 70% of maternal lymphocytes during pregnancy, occupying both the decidua basalis of the endometrium at the implantation site and the mesometrial lymphoid aggregate of pregnancy that surrounds the blood vessels supplying the placenta. This number is at its peak in early pregnancy but declines at parturition.
Morphology
General
Most studies of uNKs use murine cells to model the human equivalent: unless stated otherwise, this section focuses on murine uNKs only. uNKs are large, granular, rounded or oval lymphocytes. On microscopic examination, they may have one or more cytoplasmic projections and/or be binucleate. Characteristically they contain eosinophilic granules that stain darkly with PAS, indicating the presence of glycoproteins. These granules usually appear regular, and they grow in size and number until approximately 2 weeks of gestation. Granules differ between species, with rat uNK cells displaying an increased number of small granules than murine cells. Rat uNK morphology also differs from the mouse due to the common occurrence of myelin within the granules. In all species, as active cells, they have numerous prominent organelles including mitochondria, well-developed golgi apparatus, free ribosomes and rough endoplasmic reticulum.
Receptors and surface proteins
Human uNKs share many of the surface receptors and proteins of circulating Natural Killer cells, exhibiting high levels of CD94 and CD56. However, they possess a unique expression profile of certain proteins, specifically CD9, CD103 and killer immunoglobulin-like receptors. Notably, mouse models suggest that they lack CD16 and L-selectin, proteins that are prominent on pNKs. There are also integrin families present in the membrane of uNK cells, the binding of which induces certain uNK-specific effects. As with cNKs, uNKs also express ILT genes and the recently discovered NCRs.
Origin
In humans, the uNK cell population is low during the proliferative phase of the menstrual cycle. The number of uNK cells increases post-ovulatory by the migration of circulating NK cells, as well as differentiation of haematopoietic stem cells. The population of NK cells in the uterine tissue will only persist if pregnancy occurs.
Origin of uNK cells during pregnancy
Based on studies using mouse models, both tissue resident Natural Killer cells and cNK cells are thought to contribute to the uNK cell population during pregnancy. The origin of uNK cells has been suggested to occur in two phases dependent on the stage of uterine tissue remodelling. At the onset of decidualisation, local proliferation of tissue resident NK cells occurs with little involvement from circulating NK cells. During the formation of the placenta, circulating NK cells are recruited.
Functions
uNK cells have an important role during pregnancy in both, humans and in mice. However, unlike NK cells, uNK’s do not have a fundamental role in the innate immune system and therefore, are not cytotoxic. Throughout pregnancy, there is adaptation of the uterus to allow the growth of the foetus to occur. Studies in mice have shown that uNK have a key role in this remodelling. During the remodelling, spiral arteries undergo structural changes to allow adequate nutritional substances to supply the growing foetus. In the mouse uNK cells were also found to produce growth-promoting factors which are important in early development before the placenta is fully formed.
Localisation
uNKs accumulate during pregnancy, and this is thought to be the result of a two-wave process, beginning with proliferation of tissue resident natural killer cells in the decidua basalis, with minimal contribution to this pool from circulating natural killer cells from the blood stream. Later during placentation, cNKs are thought to be recruited to aid with vascular remodelling. These cells are attracted to the uterus during pregnancy independent of chemokine receptors CCR-2 and CCR-5 in spite of these being important in recruitment of other inflammatory responses, and the exact method of their homing is yet to be understood.
Role in disease
uNKs secrete trophoblast invasion promoting cytokines and various angiogenic factors required for remodelling maternal spinal arteries in order to support sufficient perfusion of the placenta in later pregnancy. Failure of this to occur can lead to miscarriage or pre-eclampsia.
