Effector functions of human decidual NK cells in healthy early pregnancy are dependent on the specific engagement of natural cytotoxicity receptors

Natural killer (NK) cells represent the major lymphocyte population in the decidua basalis of the human uterus during healthy early pregnancy. The activity of decidual NK (dNK) cells and their activation status are different from those of peripheral blood (PB)-NK cells; i.e. dNK cells exhibit a unique phenotype. Decidual NK cells have been defined as CD56bright, CD16neg, and more recently CD160neg. They express a unique repertoire of NK cell receptors, identical among all donors tested. Decidual NK cells express in particular NKp46-, NKp30- and NKp44-activating receptors, contrasting with PB-NK cells which are devoid of NKp44-activating receptors. Specific engagement of each of these three so-called natural cytotoxicity receptors in dNK cells has important functional consequences in terms of cytokine, chemokine and angiogenic factor secretion as well as cytotoxic potential. Strikingly, and in contrast with PB-NK cells, engagement of NKp46- but not NKp30-activating receptor on freshly isolated dNK cells triggers cytotoxicity. Such cytotoxic potential of dNK cells is negatively controlled by NKG2A inhibitory receptor co-engagement. This suggests that in situ, dNK cells cannot kill trophoblast cells during normal pregnancy. Whether such NKG2A-mediated inhibition is abolished during pregnancies complicated by pathologies including viral infection is an interesting hypothesis that remains to be tested.