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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.

Pregnancy immunogenetics: NK cell education in the womb?