Maternal Decidual Macrophages Inhibit NK Cell Killing of Invasive Cytotrophoblasts During Human Pregnancy
Human pregnancy is an immunological paradox. Semi-allogeneic (fetal) placental cells (extravillous cytotrophoblasts; CTBs) invade the uterine lining (decidua), which contains a unique decidual Natural Killer (dNK) cell population, identified by the cell-surface phenotype CD56(bright)CD16(-)CD3(-) and CD14(+) CD206(+) macrophages (dMac). Previous reports suggested that human dNK cells are not a threat to the feto-placental unit because they are anergic. In contrast, here we showed that purified and exogenously stimulated dNK cells are capable killers of cellular targets, including semi-allogeneic CTBs. However, dMacs in the decidual leukocyte (DL) population restrained dNK killing through a Transforming Growth Factor (TGF)-β1-dependent mechanism. Our findings support a new model whereby dNK cells, capable of killing CTBs, are prevented from doing so by neighboring macrophages, thus protecting the fetal cells from NK cell attack. We speculate that this mechanism would inhibit dNK cell-mediated killing, even in conditions where high levels of cytokines may stimulate dNK cells, which could pose a threat to the developing placenta.