NKG2A Educates Uterine NK Cells to Optimise Pregnancy in Humans and Mice

Education of natural killer (NK) cells is a genetically determined process that primes NK-cell activity upon the binding of their inhibitory receptors to self-ligands. Although NK-cell education is predictable and measurable in the laboratory, its biological significance is unknown. Here we show that the inhibitory NK cell receptor NKG2A protected against the hypertensive disorder of pregnancy pre-eclampsia in individuals genetically programmed to favour the engagement of NKG2A with its ligand HLA-E. Using NKG2A-deficient Klrc1-/- mice, we show that NKG2A was required to educate uterine NK cells to regulate uterine vascular adaptation to pregnancy, placental function and transcriptome, as well as fetal growth. Immune checkpoint blockade of NKG2A during pregnancy in wild-type mice did not affect fetal growth, suggesting acute ablation of this pathway does not interfere with pregnancy outcome.