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 5

Activation of KIR2DS1 by HLA-C2 or crosslinking results in GM-CSF production.

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Activation of KIR2DS1 by HLA-C2 or crosslinking results in GM-CSF produc...
(A) Intracellular staining for GM-CSF in KIR2DL1/S1 subsets after coculture of dNK with 221-C2 targets. Frequencies of GM-CSF+ dNK were compared between different subsets: KIR2DS1sp with no other NKRs expressed (2DS1sp NKR–), KIR2DS1sp that do coexpress other NKRs apart from KIR2DL1 (2DS1sp NKR+), and dp cells without other NKRs (dp NKR–). GM-CSF staining in KIR2DL1sp and dn subsets was similar to that in the dp subset (data not shown). **P < 0.01, Mann-Whitney test. (B) Increased GM-CSF secretion in supernatants of dNK from KIR2DS1+ donors after antibody crosslinking. Total dNK from KIR2DS1+ or KIR2DS1-ve donors were crosslinked for 12 hours with EB6 or IgG control and GM-CSF measured in supernatants by ELISA. *P < 0.05, Wilcoxon signed rank test.