The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice

The conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and similar to 50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development. These are features of the human syndrome preeclampsia. In a genome-wide association study of 7,219 pre-eclampsia cases, we found a 7% greater relative risk associated with the maternal HLA-B allele that does not favor NKG2A education. These results show that the maternal HLA-B -> HLA-E -> NKG2A pathway contributes to healthy pregnancy and may have repercussions on offspring health, thus establishing the physiological relevance for NK cell education.

Automated summary

Genetic ablation of NKG2A in dams mated with wild-type males may result in suboptimal maternal vascular responses during pregnancy, leading to various abnormalities similar to human preeclampsia. The study also suggests that the maternal HLA-B allele plays a significant role in influencing NKG2A education, potentially affecting the risk of developing preeclampsia.