Figure 1.

A summary of the role of uterine natural killer (uNK) cells on the events entailed in successful embryo implantation and maintenance of a pregnancy, as well as on the pathophysiological mechanisms involved on recurrent implantation failure (RIF) and recurrent miscarriage (RM), respectively. (A) Successful implantation and pregnancy maintenance. In physiological conditions, uNK subpopulations presenting with low cytotoxicity constitute the predominant leucocyte population in the decidua. During implantation, uNK cells interact with the extravillous trophoblast cells (EVTs), acknowledging the human leukocyte antigens G (HLA-G) via their killer cell immunoglobulin-like (KIR) receptors. These interactions are essential for several reasons. To begin with, these interactions lead to maternal immunological accommodation of the semi-allogeneic fetus, establishing an interface between the mother and the fetus. Additionally, these interactions trigger uNK cells to secrete several cytokines and growth hormones, promoting trophoblast invasion. Following their triggering, uNK cells secrete several matrix metalloproteinases (MMPs) and angiogenic factors, such as vascular endothelial growth factor (VEGF), regulating remodeling of the spiral arteries. Successful implementation of these events is essential for achieving implantation and pregnancy maintenance. In summary, uNK cells constitute master regulators of the events entailed during embryo immunological acceptance during EVTs invasion as well as during spiral arteries’ remodeling. (B) Events entailed in implantation failure leading to inadequate pregnancy maintenance in RIF and RM. When uNK cells present with increased numbers and/or with an abnormally increased cytotoxic phenotype, all the events entailed in normal embryo implantation are dysregulated. Due to their increased cytotoxic phenotype, this abnormal uNK cells subpopulation fails to appropriately interact with EVT cells, and instead they attack and destroy EVTs. Furthermore, secretion of growth hormones and cytokines by abnormal uNK cells is compromised, reducing EVTs invasion into the decidua. Ultimately, abnormal uNK cells fail to promote spiral arteries remodeling. These events lead to implantation failure or to impaired pregnancy maintenance, eventually resulting in miscarriage. RIF: recurrent implantation failure; RM: recurrent miscarriage; uNK: uterine natural killer cells; EVT: extravillous trophoblast; HLA-G: human leukocyte antigen G; KIR: killer cell immunoglobulin-like receptor; MMPs: matrix metalloproteinases; VEGF: vascular endothelial growth factor.