Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2

Abstract

Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells -specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells -influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2 + trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success. IntroductionThe main tissue location where maternal allo-recognition of the fetus occurs is in the uterus at the site of placentation, where fetal extravillous trophoblast cells (EVTs) invade and intermingle with maternal leukocytes (1). Uterine NK (uNK) cells account for approximately 70% of decidual leukocytes and are likely to be involved in placentation and thus fetal growth and development. We proposed that placentation is regulated as a result of interactions between maternal killer immunoglobulin-like receptors (KIRs) expressed by uNK cells and their cognate ligands, HLA-C molecules, displayed by invading fetal trophoblast cells (2, 3). The importance of NK cell KIR/HLA-C interactions in mediating allorecognition in the artificial context of BM transplantation (BMT) is well known (4). The only physiological situation in which NK allo-recognition occurs is during pregnancy.The function of EVT is to access the maternal blood supply during placentation, when trophoblast invades the walls of the spiral arteries, converting them to high-conductance vessels (1).

The placenta: a multifaceted, transient organ

“…However, the deep invasion comes at a price, for it is associated with an increased risk of complications of pregnancy, such as pre-eclampsia [89]. Recent evidence shows these complications have, in part, an immunological basis [45], as explored in other contributions to this themed issue. Adoption of the upright posture may be another contributor, for it poses unique haemodynamic challenges to the placental circulations [90].…”

“…There is a carefully orchestrated dialogue between the two cell types involving polymorphic HLA-C ligands on the trophoblast and killer-cell immunoglobulin-like receptors (KIRs) on the uNK cells. Certain combinations of ligand and receptor are associated with an increased risk of complications of pregnancy, including miscarriage, pre-eclampsia and growth restriction [45].…”

The role of the maternal immune system in the regulation of human birthweight

“…Our results show that there is a consistent relationship between particular combinations of maternal KIR and fetal HLA-C ligands and birthweight [3,35,37,38]. We compared maternal KIR and fetal HLA-C genotypes from a large number of first pregnancies selected from the Norwegian Mother -Baby cohort (MoBa) with known birthweight corrected for gestational age and fetal sex.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Although disease associations27, 76, 124, 125 and sequence homology67 with their inhibitory counterparts suggest that activating KIR recognize HLA class I, their cognate ligands have been harder to identify (Fig. 1).…”