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 ∼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 pre-eclampsia. 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. [Display omitted] [Display omitted] •CD94/NKG2A educates uterine NK cells•NKG2A-deficient dams display reduced utero-placental hemodynamic adaptations•Asymmetric growth restriction and abnormal brain development in NKG2A-deficient dams•Non-functional HLA-B→HLA-E→NKG2A pathway exposes women to greater pre-eclampsia risk The physiological importance of NK cell education is unclear. Shreeve et al. show that the CD94/NKG2A receptor educates maternal NK cells to orchestrate vascular changes leading to normal fetal brain development and, in humans, to lower risk of complicated pregnancy.