Uterine natural killer cells and pregnancy outcomes: mechanisms, biomarkers, and therapeutic targets

Uterine natural killer cells (uNK) represent the dominant population of immune cells in the decidual tissue during early pregnancy, playing a key role in embryo implantation, spiral artery remodeling, and the establishment of proper uteroplacental blood flow. Unlike peripheral natural killer cells (pNK), uNK cells exhibit limited cytotoxicity and pronounced regulatory functions mediated through the production of cytokines, growth factors, and adhesion molecules. An imbalance in uNK cell activation or inhibition is associated with developing several pregnancy complications, including recurrent pregnancy loss, preeclampsia, and infertility associated with endometriosis. Here, we analyze current concepts assessing uNK cell phenotype and functional activity, crosstalk with trophoblasts and regulatory T cells (Treg), as well as the role for key receptors – NKp46 (natural killer protein 46), NKp44 (natural killer protein 44), NKp30 (natural killer protein 30), CD16 (cluster of differentiation 16), NKG2A (natural killer group 2 member A receptor), and cognate ligand HLA-E (human leukocyte antigen E). Special attention is paid to biomarkers reflecting uNK cell status and their prognostic value in reproductive medicine. Therapeutic approaches aimed at modulating uNK cell activity are also considered. In particular, it has been shown that the use of glucocorticoids (e.g., prednisolone) reduces endometrial CD56⁺ uNK cell counts and is applied in patients with recurrent pregnancy loss and repeated implantation failure. Granulocyte colony-stimulating factor (G-CSF) is capable of stimulating angiogenesis, enhancing endometrial receptivity, and increasing the clinical pregnancy rate in women with impaired uNK function. Monoclonal antibodies targeting activating NK cell receptors (NKp46, NKp44, NKp30, CD16) are considered an experimental approach to alleviate excessive uNK cytotoxicity in endometriosis and recurrent miscarriage. Another promising direction relies on applying targeted intervention in immune checkpoints, particularly modulating interaction between the NKG2A receptor and its ligand HLA-E, which may optimize spiral artery remodeling and uteroplacental blood flow.