NKG2A educates uterine NK cells to optimise pregnancy outcomes in humans and mice

Abstract The conserved CD94/NKG2A receptor binds HLA-E in humans and Qa-1 in mice. Besides inhibiting natural killer (NK) cell activation, NKG2A drives NK-cell education, a process influenced by HLA-B alleles that promotes NK cell function. In human populations some individuals are genetically programmed to favour NKG2A education and have more robust NK cell function. NKG2A is expressed by nearly all human and roughly half mouse uterine NK cells (uNK), but the importance of NK-cell education in physiology is unknown. Here we show that NKG2A was required for uNK cell-education in dams. Genetic ablation of NKG2A caused sub-optimal vascular responses in pregnancy, increased rate of smaller fetuses, which grew asymmetrically with abnormal brain development, and changes in placental gene expression consistent with stress. These are features of the human syndrome pre-eclampsia. In a genome-wide association study of 7,219 cases and 155,660 control pregnancies, we found that the maternal HLA-B allele that does not favour NKG2A education, was associated with a 7% greater relative risk of pre-eclampsia (P=0.005, OR= 1.07). These results establish the relevance of NK cell education in physiology and show that the maternal HLA-B –> HLA-E –> NKG2A pathway contributes to healthy pregnancy and may influence offspring health.