How Do Uterine Natural Killer and Innate Lymphoid Cells Contribute to Successful Pregnancy?

Abstract

Innate lymphoid cells (ILCs) are the most abundant immune cells in the uterine mucosa both before and during pregnancy. Circumstantial evidence suggests they play important roles in regulating placental development but exactly how they contribute to the successful outcome of pregnancy is still unclear. Uterine ILCs (uILCs) include subsets of tissue-resident natural killer (NK) cells and ILCs, and until recently the phenotype and functions of uILCs were poorly defined. Determining the specific roles of each subset is intrinsically challenging because of the rapidly changing nature of the tissue both during the menstrual cycle and pregnancy. Single-cell RNA sequencing (scRNAseq) and high dimensional flow and mass cytometry approaches have recently been used to analyse uILC populations in the uterus in both humans and mice. This detailed characterisation has significantly changed our understanding of the heterogeneity within the uILC compartment. It will also enable key clinical questions to be addressed including whether specific uILC subsets are altered in infertility, miscarriage and pregnancy disorders such as foetal growth restriction and pre-eclampsia. Here, we summarise recent advances in our understanding of the phenotypic and functional diversity of uILCs in non-pregnant endometrium and first trimester decidua, and review how these cells may contribute to successful placental development.

The Role of Uterine Natural Killer Cells on Recurrent Miscarriage and Recurrent Implantation Failure: From Pathophysiology to Treatment

“…Is there a biological interpretation behind the diversity of phenotypes? [121] Routinely offering therapies targeting uNK cells fails to be justified by strong evidence, and recommendations that, respectively, advise against such practices should be taken into consideration. Future research is imperative to demonstrate the exact role of uNK cells in the pathophysiology of RIF and RM.…”

Editorial: Veterinary Reproductive Immunology

“…The work led by Anne Croy showed the essential role that the trophoblast layer of the placenta plays in maintaining interspecies pregnancies ( 43 ). Furthermore, Croy's team ( 44 ) and Moffett's group ( 45 , 46 ) provided evidence for the importance of uterine Natural Killer cells, dendritic cells ( 47 ), and innate uterine lymphoid cells [reviewed in ( 48 )] for successful pregnancies in mice and humans, highlighting the importance of innate immune cells in the physiology of gestation. Besides, the works by Antczak and Allen on the compromise of the maternal immune response in the developing chorionic girdles in equine placentation in the early 80's ( 49 , 50 ) provided evidence for the importance of cells of the adaptive immune system in successful placental development and fetal growth in mares.…”

Unique Aspects of Human Placentation

“…Instead, trophoblasts of the giant cell lineage migrate to and line the spiral arteries [ 54 ]. However, this does not occur until vascular remodelling is complete [ 5 , 55 ]. Indeed, rodents are unsatisfactory models of trophoblast invasion.…”

“…The section on placental immunology therefore focuses mainly on the uterine natural killer (uNK) cells and their ligands. Information on other immune cells, including macrophages, T-cells and innate lymphoid cells, should be sought elsewhere [ 5 , 6 ].…”