Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies

Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-γ and VEGFα, with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. [Display omitted] •A unique subset of human natural killer cells exists in repeated pregnancies•These NK cells, termed PTdNKs, express increased amounts of NKG2C and LILRB1•PTdNKs secrete increased levels of IFN-γ and VEGFα; the latter supports vascularization Natural killer cells are present in the human decidua, regulating trophoblast invasion and angiogenesis. Here, Gamliel et al. report on a special subset of human decidual natural killer cells, which “remember” pregnancy and better support subsequent pregnancies. This might explain why first pregnancies are at increased risk of developing diseases of poor placentation.