American Association of Immunologists, The Journal of Immunology, 11(197), p. 4292-4300, 2016
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Tissue-specific NK cells are abundant in the pregnant uterus and interact with invading placental trophoblast cells that transform the maternal arteries to increase the fetoplacental blood supply. Genetic case-control studies have implicated killer cell Ig-like receptor (KIR) genes and their $\textit{HLA}$ ligands in pregnancy disorders characterized by failure of trophoblast arterial transformation. Activating $\textit{KIR2DS1}$ or $\textit{KIR2DS5}$ (when located in the centromeric region as in Africans) lower the risk of disorders when there is a fetal $\textit{HLA-C}$ allele carrying a C2 epitope. In this study, we investigated another activating $\textit{KIR, KIR2DS4}$, and provide genetic evidence for a similar effect when carried with $\textit{KIR2DS1. KIR2DS4}$ is expressed by ∼45% of uterine NK (uNK) cells. Similarly to KIR2DS1, triggering of KIR2DS4 on uNK cells led to secretion of GM-CSF and other chemokines, known to promote placental trophoblast invasion. Additionally, XCL1 and CCL1, identified in a screen of 120 different cytokines, were consistently secreted upon activation of KIR2DS4 on uNK cells. Inhibitory $\textit{KIR2DL5A}$, carried in linkage disequilibrium with $\textit{KIR2DS1}$, is expressed by peripheral blood NK cells but not by uNK cells, highlighting the unique phenotype of uNK cells compared with peripheral blood NK cells. That KIR2DS4, KIR2DS1, and some alleles of KIR2DS5 contribute to successful pregnancy suggests that activation of uNK cells by KIR binding to HLA-C is a generic mechanism promoting trophoblast invasion into the decidua. ; Other ; This work was supported by the Wellcome Trust, the Centre for Trophoblast Research, the British Heart Foundation, and the Cambridge Philosophical Society.