Pathways Participating in Activation of Mouse Uterine Natural Killer Cells During Pregnancy

Activated natural killer (NK) cells proliferate in large numbers in murine mesometrial endometrium from Day 6 to Day 12 of gestation (term = 19 gestation days) to become the most abundant uterine lymphocytes. Early human decidua contains analogous CD56+/CD16– cells. Murine uterine (u)NK cells localize to decidua basalis and mesometrial lymphoid aggregate of pregnancy (MLAp). Decidua and MLAp are transient, pregnancy-associated tissues traversed by maternal arteries to the placentas. Uterine NK cells sensitize these arteries, facilitating their structural changes into high-volume conduits by Gestation Day 10 through release of interleukin (IL)-18, interferon (IFN)-(gamma), vascular endothelial growth factor (VEGF), and other molecules. Little information exists concerning where, when, or how murine or human uNK cells become activated. In murine lymphoid tissue, three NK cell adaptor-mediated activation pathways are known: FcR (gamma)/CD3(zeta)DNAX-activating protein (DAP) 10, and DAP12 (genes Fcgr3/Cd3z, Hcst, and Tyrobp, respectively). Expression of ligands for these receptors was demonstrated in implantation sites of normal C57BL/6J mice. Then, histological and morphometric analyses of implantation sites in mice with genetic inactivation of each pathway were undertaken. Implantation sites in DAP10–/– (Hcst deleted) mice appeared normal, spiral artery modification occurred, and concentrations of IFN-(gamma) in MLAp and decidua basalis were similar to those in time-matched C57BL/6J. Implantation sites of FcR(gamma)–/–/CD3(zeta)–/– (Fcgr3/Cd3z double knockout), DAP12 (Tyrobp)-loss-of-function-mutant, and FcR(gamma)–/–/DAP12–/– (Fcgr3/Tyrobp double knockout) mice differentiated abundant but functionally impaired uNK cells that could not modify spiral arteries. These data reveal key importance of FcR(gamma)–/–/CD3(zeta)–/– and thus maternal IgG during activation of mouse uNK cells and assign DAP12 but not DAP10 signaling contributions.