Immunology

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

Abstract
Activated Natural Killer (NK) cells proliferate in large numbers in murine mesometrial endometrium from days 6-12 of gestation (term19 gestation days (gd)) 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 placentae. 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)-, 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/CD3, DAP10, 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- in MLAp and decidua basalis were similar to those in time-matched C57BL/6J. Implantation sites of FcR^-/-/CD3^-/- (Fcgr3/Cd3z double knockout), DAP12 (Tyrobp)-loss-of-function-mutant, and FcR^-/-/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^-/-/CD3^-/- and thus maternal IgG, during activation of mouse uNK cells and assign DAP12 but not DAP10 signaling contributions.

Key words: Immunology • Pregnancy • Decidua • Signal transduction • Uterus

This article has been cited by other articles:

				R. H. McIntire, K. G. Ganacias, and J. S. Hunt Programming of Human Monocytes by the Uteroplacental Environment Reproductive Sciences, May 1, 2008; 15(5): 437 - 447. [Abstract] [PDF]

				S. D. Burke, H. Dong, A. D. Hazan, and B. A. Croy Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice Diabetes, December 1, 2007; 56(12): 2919 - 2926. [Abstract] [Full Text] [PDF]