Maternal uterine NK cell–activating receptor KIR2DS1 enhances placentation
Shiqiu Xiong, … , Francesco Colucci, Ashley Moffett
Shiqiu Xiong, … , Francesco Colucci, Ashley Moffett
Published October 1, 2013; First 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 3

KIR2DS1sp dNK respond to HLA-C2+ target cells.

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KIR2DS1sp dNK respond to HLA-C2+ target cells. dNK expressing other NK...
dNK expressing other NKRs (LILRB1, KIR2DL2/L3/S2, KIR3DL1, and KIR2DS4) were gated out from the analysis, except where stated. (A) CD107a staining was measured in the 4 dNK subsets after incubation with 221-C2 target cells (n = 25). Horizontal bars indicate mean for each group. (B) Analysis similar to that in A, but performed in the presence of the HLA class I blocking mAb 6A4 or isotype control (con) (n = 6). (C) Effect of other NKRs on KIR2DS1 responses to 221-C2 targets. After culture with 221-C2 targets, KIR2DS1+ dNK were gated into 3 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–). Frequency of CD107a+ dNK was compared between the 3 different subsets (n = 24). (D) Effect of donor’s HLA-C genotype on KIR2DS1 response. Degranulation of KIR2DS1sp NKR– subset in response to culture with 221-C2 targets was compared between donors who had at least one HLA-C2 allele (C2/X, n = 19) and donors homozygous for HLA-C1 (C1/C1, n = 13). (E) Degranulation of the KIR2DS1sp NKR– subset from matched pbNK and dNK was measured after coculture with 4 different 221-C2 clones expressing different surface levels of the HLA-C2 allele Cw*0602 (Supplemental Figure 6). Clone 1 is 221-parent. Horizontal bars indicate means for 4 separate donors. (F) Degranulation of the KIR2DS1sp NKR– subset in response to the same clone of 221-C2 target cells by pbNK and dNK from the same donor (n = 18). *P < 0.05 and **P < 0.01, Mann-Whitney test (A, C, and D). *P < 0.05 and **P < 0.01, Wilcoxon paired samples test (B and F). *P < 0.05, Student’s paired t-test (E).