Absence of Natural Killer Cells during Murine Pregnancy is Associated with Reproductive Compromise in TgE26 Mice1

Abstract

Strategies of cell depletion were pursued to extend understanding of the functions of natural killer (NK) cell-like large granulated lymphocytes found in the rodent uterus during pregnancy. Repeated infusions of antibody to Ly-49G2, a surface marker thought to be expressed by the progenitor forms of these cells, removed Ly-49G2+ cells from the virgin but not the pregnant uterus. Large granulated uterine lymphocytes also differentiated during pregnancy in transgenic mice that carried a deletion in the IL-2 gene. This cell population was absent in two strains of mice, p56lck-/lck-.IL-2Rbeta-/IL-2Rbeta- and TgE26. Implantation sites in both of these strains had histopathological anomalies in the zone of decidualization. In TgE26 mice, a sudden onset of fetal loss began at Day 10 of gestation. Fetal death was associated with progressive changes in the maternal uterine arterioles, suggestive of localized arteriosclerosis associated with hypertension. TgE26 females carried immune-competent fetuses to term, apparently through preventive or compensatory mechanisms that may modify the uterine vasculature after the onset of vascular pathology. These studies are the first to suggest a vital role for large granulated lymphocytes in the promotion of fetal survival and pregnancy success.

Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth

“…uNK cells support neovascularization of the decidua by producing proangiogenic and endothelial mitogenic stimulants and contribute to arterial transformation by initiating the loss of the arterial media (5,14,18,19). In uNK cell-deficient mice the arteries do not undergo the dilation that is normally observed during pregnancy, and the resulting decrease in maternal blood supply may be associated with small placental size and embryonic lethality (20,21). Thus, normal progression of pregnancy seems to be influenced by the functional activity of uNK cells, which in turn may be regulated by the paternal MHC expression on trophoblast through direct or indirect interactions.…”

Infection of pregnant mice with Listeria monocytogenes induces fetal bradycardia

“…The etiologies and predictors of miscarriage are complex, and, therefore, predictable models need to be developed and evaluated with great care. Models of preterm abortion include the use of toxins or genetic mouse models in which a percentage of fetuses are lost (1,2). The investigation of the details in such models has generally been approached in a manner that precludes the observation of both the cause and effect in the same animal.…”

“…Post facto determination of the cause of a given miscarriage, although important, cannot address mechanisms or means of prevention as directly as experimental investigation. Several animal models of miscarriage have been developed (1,2), but this event is not always predictable even in a laboratory setting. The complex interaction between mother and fetus represents a challenging research problem, and the inability to obtain early data from human miscarriages has greatly impeded our knowledge of this tragic event.…”

NK cells, hypoxia and trophoblast cell differentiation

“…From the mouse genetic models, we learned that NK cells promote uterine spiral artery remodeling, including decreasing arterial smooth muscle wall thickness and increasing vessel lumen diameter. 15 NK cell immunodepletion in the rat results in striking changes in the uterine spiral arteries, these hypoxia-stimulated actions are mediated by the transcription factor complex, hypoxia-inducible factor (HIF). 14,25 HIFs are basic helix loop helix Per-Arnt/AhRSim (bHLH-PAS) transcription factors.…”