Maternal uterine NK cell–activating receptor KIR2DS1 enhances placentation
Shiqiu Xiong, … , Francesco Colucci, Ashley Moffett
Shiqiu Xiong, … , Francesco Colucci, Ashley Moffett
Published September 16, 2013
Citation Information: J Clin Invest. 2013;123(10):4264-4272. https://doi.org/10.1172/JCI68991.
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Research Article Reproductive biology

Maternal uterine NK cell–activating receptor KIR2DS1 enhances placentation

Abstract

Reduced trophoblast invasion and vascular conversion in decidua are thought to be the primary defect of common pregnancy disorders including preeclampsia and fetal growth restriction. Genetic studies suggest these conditions are linked to combinations of polymorphic killer cell Ig-like receptor (KIR) genes expressed by maternal decidual NK cells (dNK) and HLA-C genes expressed by fetal trophoblast. Inhibitory KIR2DL1 and activating KIR2DS1 both bind HLA-C2, but confer increased risk or protection from pregnancy disorders, respectively. The mechanisms underlying these genetic associations with opposing outcomes are unknown. We show that KIR2DS1 is highly expressed in dNK, stimulating strong activation of KIR2DS1+ dNK. We used microarrays to identify additional responses triggered by binding of KIR2DS1 or KIR2DL1 to HLA-C2 and found different responses in dNK coexpressing KIR2DS1 with KIR2DL1 compared with dNK only expressing KIR2DL1. Activation of KIR2DS1+ dNK by HLA-C2 stimulated production of soluble products including GM-CSF, detected by intracellular FACS and ELISA. We demonstrated that GM-CSF enhanced migration of primary trophoblast and JEG-3 trophoblast cells in vitro. These findings provide a molecular mechanism explaining how recognition of HLA class I molecules on fetal trophoblast by an activating KIR on maternal dNK may be beneficial for placentation.

Authors

Shiqiu Xiong, Andrew M. Sharkey, Philippa R. Kennedy, Lucy Gardner, Lydia E. Farrell, Olympe Chazara, Julien Bauer, Susan E. Hiby, Francesco Colucci, Ashley Moffett

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Figure 1

Frequency of KIR2DS1+ and KIR2DL1+ dNK is increased compared with pbNK from the same donors and KIR2DS1 is functional in dNK.

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Frequency of KIR2DS1+ and KIR2DL1+ dNK is increased compared with pbNK f...
(A) Freshly isolated leukocytes from decidua or peripheral blood were gated on live, CD56+CD3– cells and examined for KIR2DS1 and KIR2DL1 expression using mAbs EB6 and 143211. dNK are shown and were also gated on CD9+ cells to avoid contamination with pbNK. (B) Overall frequency of NK cells positive for KIR2DL1 or KIR2DS1 in paired samples from blood and decidua expressed as a percentage of total NK cells (n = 13). (C) Blood or dNK were classified into 4 subsets: KIR2DS1sp, dp, KIR2DL1sp, and dn as shown in A. The frequency of each subset as a percentage of total NK cells was determined in paired samples of fresh NK cells from blood or decidua (data for dn subset not shown, n = 13). Horizontal bars show mean for each group. (D) The responsiveness of the KIR2DS1sp, KIR2DL1sp, and dp dNK subsets was measured by stimulating either with control IgG (IgG con) or with mAb 11PB6, which crosslinks both KIR2DS1 and KIR2DL1. Degranulation was assessed by staining for surface CD107a or control IgG (n = 5). KIR2DL1 and KIR2DS1 subsets were gated after FACS staining, as shown in A and will thus express a variety of other NK receptors. Basal responses were seen in the dn subset (data not shown). *P < 0.05 and **P < 0.01, Wilcoxon paired samples test. 2DS1sp, KIR2DS1sp; 2DL1sp, KIR2DL1sp; dp, KIR2DL1+KIR2DS1+.