Pregnancy immunogenetics: NK cell education in the womb?

Abstract

During embryo implantation and initiation of pregnancy, uterine NK (uNK) cells engage invasive fetal trophoblasts to remodel vessels that conduct blood to the placenta. This partnership, involving uNK cell receptors that recognize HLA-C ligands on trophoblasts, varies the course of human pregnancy because the genes for both receptors and ligands are extraordinarily diverse. Several pregnancy disorders are attributed to insufficient trophoblast invasion and the limitation it imposes on human reproduction. Previously, a particular combination of fetal HLA-C and maternal inhibitory uNK cell receptor was associated with predisposition for preeclampsia. In this issue of the JCI, Hiby and colleagues extend this correlation to recurrent miscarriage and fetal growth restriction, revealing the common mechanism underlying these common pregnancy syndromes. Equally important, they show that mothers with an activating receptor of similar specificity to the inhibitory receptor are less likely to suffer disordered pregnancy.

Figure 1. The human KIR locus consists of centromeric and telomeric regions that recombine to produce A and B haplotypes with a distinctive gene content.

Structures of common haplotypes are shown in the top panel. Gray boxes indicate conserved framework genes; red boxes indicate genes characteristic of A haplotypes; blue boxes indicate B haplotype–specific genes. The centromeric (Cen) and telomeric (Tel) gene-content motifs are listed at left. The symbol at the boundary between the centromeric and telomeric regions represents a repetitive sequence, the site for meiotic recombination that has shuffled the centromeric and telomeric motifs. The bottom panel illustrates HLA-C–specific KIRs and their specificities for the C1 and C2 epitopes. Yellow indicates inhibitory receptors KIR2DL2/3 and KIR2DL1; green indicates the activating receptor KIR2DS1.