Role of Decidual Natural Killer Cells in Human Pregnancy and Related Pregnancy Complications

Abstract

Pregnancy is a unique type of immunological process. Healthy pregnancy is associated with a series of inflammatory events: implantation (inflammation), gestation (anti-inflammation), and parturition (inflammation). As the most abundant leukocytes during pregnancy, natural killer (NK) cells are recruited and activated by ovarian hormones and have pivotal roles throughout pregnancy. During the first trimester, NK cells represent up to 50–70% of decidua lymphocytes. Differently from peripheral-blood NK cells, decidual natural killer (dNK) cells are poorly cytolytic, and they release cytokines/chemokines that induce trophoblast invasion, tissue remodeling, embryonic development, and placentation. NK cells can also shift to a cytotoxic identity and carry out immune defense if infected in utero by pathogens. At late gestation, premature activation of NK cells can lead to a breakdown of tolerance of the maternal–fetal interface and, subsequently, can result in preterm birth. This review is focused on the role of dNK cells in normal pregnancy and pathological pregnancy, including preeclampsia, recurrent spontaneous abortion, endometriosis, and recurrent implantation failure. dNK cells could be targets for the treatment of pregnancy complications.

Characterization of Epigenetic and Molecular Factors in Endometrium of Females with Infertility

“…It was shown that the number of cytotoxic uNK cell-surface receptors on uNK cells and increased number of immature uNK cells was upregulated in the endometrium of infertile females with endometriosis, compared to fertile females. Moreover, NKp44 expression on uNK cells was significantly increased in RIF patients and indicated that NK cells’ cytotoxicity may cause the recurrent implantation failure [ 39 , 40 , 41 ].…”

Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation

“…In general, there is no uniform evidence that the above-mentioned immunotherapeutic approaches benefit clinical outcomes in patients; and there is no consensus on the role of uNK cells in RM or RIF ( 180 ). However, recent studies have shown that uNK cells have special physiological functions in reproduction, especially in the establishment and maintenance of pregnancy ( 182 , 183 ), and corticosteroids/intralipid therapy that suppress NK cells activity may exacerbate pregnancy failure ( 184 , 185 ). Additionally, the state of the endometrium or the risk of pregnancy disease may be predicted by the examination of uNK cells in menstrual blood ( 25 ).…”

Plasticity of NK cells in Cancer

“…Physiologically, dNK cells are crucial to successful placentation through the orchestration of trophoblast invasion and endometrial vasculature remodelling. Although not entirely understood, dNK cells are thought to be important for the induction of immune tolerance and maintaining a tolerogenic environment at the maternal decidua ( 47 ). Given their specialised nature, it is no surprise that dNK cells have a unique functional phenotype.…”

“…Most notably, dNK cells produce an array of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and angiopoietin-2 (Ang-2). In addition, dNK cells produce various immunoregulatory cytokines such as, transforming growth factor beta (TGFβ), GM-CSF, IL-8, and IL-10 ( 47 ), and are poorly cytolytic ( 46 ). Considering this, tumor-infiltrating NK cells displaying a dNK-like phenotype are unlikely to result in beneficial disease outcomes ( Figure 2 ).…”