Abstract
The presence of unusual natural killer cells in human endometrium has been recognized for 30 years, but despite considerable research effort, the in vivo role of uterine natural killer (uNK) cells in both normal and pathological pregnancy remains uncertain. uNK cells may differentiate from precursors present in endometrium, but migration from peripheral blood in response to chemokine stimuli with in situ modification to a uNK cell phenotype is also possible. uNK cells produce a wide range of secretory products with diverse effects on trophoblast and spiral arteries which may play an important role in implantation and early placentation. Interactions with other decidual cell populations are also becoming clear. Recent evidence has demonstrated subpopulations of uNK cells and the presence of other innate lymphoid cell populations in decidua which may refine future approaches to investigation of the role of uNK cells in human pregnancy.
Highlights
Granulated cells were recognized in endometrial stroma almost a century ago, but despite light and electron microscopic evidence for a lymphocyte origin in humans[1], mouse[2,3], and rat[4], they were regarded as stromal cells until identified as unusual natural killer (NK) cells using monoclonal antibodies[5,6,7]
Pre-eclampsia, fetal growth restriction, and recurrent pregnancy failure have been associated with altered uterine natural killer (uNK) cell numbers and function and specific killer immunoglobulin-like receptors (KIRs)/HLA-C combinations but the significance of these observations is not fully established. uNK cells produce a wide range of chemokines, cytokines, growth factors, and matrix metalloprotease (MMP), and many have been shown to have specific effects on trophoblast or spiral arteries, but in vivo translation is difficult
The starting point for most studies of uNK cell function is decidua retrieved from pregnancy terminations or miscarriages. uNK cells within these samples have been exposed directly to extravillous trophoblast (EVT) or to soluble HLA-G with possible functional effects
Summary
Granulated cells were recognized in endometrial stroma almost a century ago, but despite light and electron microscopic evidence for a lymphocyte origin in humans[1], mouse[2,3], and rat[4], they were regarded as stromal cells until identified as unusual natural killer (NK) cells using monoclonal antibodies[5,6,7]. UNK cells from 9- to 14-week gestational age pregnancies with abnormal Doppler wave forms showed reduced expression of KIR2DL/S1,3,5 and LILRB185, reduced stimulation of trophoblast outgrowth from villous explants[83], reduced in vitro induction of apoptosis in vascular smooth muscle cells and endothelial cells[82], increased angiogenic growth factor secretion[84], and reduced ability to destabilize endothelial structures[103] These results all suggest that uNK cells from pregnancies at increased risk of pre-eclampsia display altered effects on trophoblast invasion and spiral arteries and emphasize the likely importance of uNK cells in early pregnancy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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