Activating KIR2DS4 Is Expressed by Uterine NK Cells and Contributes to Successful Pregnancy.

Philippa R Kennedy,Martin A Ivarsson,Susan E Hiby,Francesco Colucci,Andrew M Sharkey,Shiqiu Xiong,Olympe Chazara,Ashley Moffett,Lucy Gardner,Lydia E Farrell

doi:10.4049/jimmunol.1601279

Abstract

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 HLA ligands in pregnancy disorders characterized by failure of trophoblast arterial transformation. Activating KIR2DS1 or KIR2DS5 (when located in the centromeric region as in Africans) lower the risk of disorders when there is a fetal HLA-C allele carrying a C2 epitope. In this study, we investigated another activating KIR, KIR2DS4, and provide genetic evidence for a similar effect when carried with 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 KIR2DL5A, carried in linkage disequilibrium with 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.

Highlights

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Binding of KIR2DS4 on decidual NK (dNK) cells to trophoblast HLA-C ligands might affect the frequency of KIR2DS4+ cells, but we find no difference in the proportion of dNK cells expressing KIR2DS4 when the mother or fetus carries its ligands (Supplemental Fig. 3A, 3B)
We have shown that KIR2DS4wt is associated with lower risk of pregnancy disorders in the presence of KIR2DS1, representing a synergistic interaction

Summary

Introduction

Genetic case-control studies have implicated killer cell Ig-like receptor (KIR) genes and their HLA ligands in pregnancy disorders characterized by failure of trophoblast arterial transformation. 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. Case-control genetic studies of Europeans have shown that pregnancy disorders that result from defective placentation with inadequate trophoblast arterial transformation (e.g., pre-eclampsia, fetal growth restriction, and recurrent miscarriage) are linked to an absence of the telomeric B (Tel-B) KIR region in the mother (Fig. 1A) and the presence of paternal C2 in the fetus [13, 18, 19].

Results

Conclusion