Killer Ig-Like Receptor Expression in Uterine NK Cells Is Biased toward Recognition of HLA-C and Alters with Gestational Age

Abstract

Immunogenetic studies suggest that interactions between maternal killer Ig-like receptor (KIR) expressed by uterine NK (uNK) cells, and fetal HLA-C molecules on trophoblast, influence the success of human placentation. However, the exact functional response of fresh uNK cells to trophoblast HLA-C molecules is unknown. In this study, we show by quantitative RT-PCR and FACS that both activating and inhibitory KIR specific for HLA-C are expressed at higher levels and on an increased proportion of NK cells in the human decidua compared with blood. In contrast, expression of KIR3DL1/S1, which is specific for HLA-B, is similar in both NK cell populations. Remarkably, there is also a temporal change in the expression pattern of HLA-C-specific KIR, with a decline in both intensity of expression and frequency on uNK cells throughout the first trimester of pregnancy. This selective up-regulation of KIR has functional consequences because uNK cells show increased binding of HLA-C tetramers compared with blood NK cells. Ab cross-linking shows that these KIR are functional and results in increased cytokine secretion. uNK cells, therefore, exhibit a unique KIR profile that enhances their ability to recognize trophoblast cells expressing HLA-C at the materno-fetal interface. This is the first report to demonstrate selective regulation of KIR expression over time in vivo in a normal physiological situation and suggests that KIR expression by uNK cells is regulated by the tissue microenvironment in the decidua.

Uterine NK cells: active regulators at the maternal-fetal interface

“…These interactions could educate NK cells or inhibit/activate them, depending on the nature of the mother's KIRs. The frequency of uNK cells expressing KIRs specific for two groups of HLA-C allotypes (C1 or C2) increases in early gestation in uNK cells compared with pbNK cells from the same woman (84)(85)(86). Thus, the uNK cell KIR repertoire is skewed toward HLA-C recognition in pregnancy, but this is not a feature of NK cells in the nonpregnant cycle (87).…”

Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes

“…This system is also considered important during pregnancy when NK cells interact with fetal and trophoblast cells expressing HLA class I to promote vascular remodeling and placentation. [6][7][8][9] KIR are highly polymorphic and individuals vary in the type and number of KIR genes they inherit. 10 Two broad classifications of KIR haplotypes exist: 'A' haplotypes are restricted in terms of the number of genes they possess and primarily encode for inhibitory receptors (KIR2DL1, KIR2DL3, KIR3DL1, KIR3DL2, KIR2DL4 and the activating gene, KIR2DS4).…”

Maternal uterine NK cell–activating receptor KIR2DS1 enhances placentation

“…Inhibitory KIR that bind to HLA-C are expressed at higher frequencies in dNK than in pbNK during early pregnancy, and dNK show increased binding to HLA-C tetramers (17)(18)(19). Conversely, KIR2DL1 and KIR2DS1 Fc-fusion proteins bind directly to primary trophoblast cells, demonstrating the possibility of allogeneic recognition of fetal trophoblast by KIR on maternal dNK (14,18).…”