A Map of Relationships Between Uterine Natural Killer Cells and Progesterone Receptor Expressing Cells During Mouse Pregnancy

Uterine natural killer (uNK) cells appear in implantation sites with decidualization. Initially, they are rare, highly proliferative cells that become abundant by midgestation and then die abruptly. Steps regulating the cyclic appearance of uNK cells are incompletely defined. Although progesterone (P4) has an essential role, mature uNK cells of women and mice lack progesterone receptors (PR). Immunohistochemical studies suggest that mouse PR− uNK cells may co-localize with PR+ stromal cells while human PR− uNK cells co-localize with immature, DC-SIGN+ dendritic cells (DCs). DCs have the potential to produce progesterone-regulated interleukin (IL)-15, a growth factor essential for uNK cells. Since the high affinity IL-15Rα is presented to differentiating NK cells in trans, requiring cell contact, histologically-detected interactions may be of central importance for uNK cell differentiation. Thus, a pregnancy time course, histological study of uNK cell differentiation and localization was undertaken in PRlacZ transgenic mice. PR+ cells and uNK cells were co-localized using LacZ histochemistry and Dolichos biflorus (DBA) lectin staining, respectively. uNK cells appeared mesometrially, where PR+ cells were rare, at gestation day 5.5. uNK cells had limited, apparently random contact with PR+ cells throughout pregnancy and never themselves expressed PR. Thus, uNK cell differentiation does not appear to require contact with PR+ cells.