Uterine natural killer cells during pregnancy in rodents

Large mononuclear cells with abundant prominent granules were described decades ago by morphologists studying implantation sites in pregnant rodents. These striking cells accumulated by midgestation in large numbers in a structure unique to rodent pregnancy that develops in the mesometrial region of the uterine musculature and was given the unfortunate name of metrial gland. Thus, the cells were originally termed granulated metrial gland (GMG) cells. Evidence provided over the last few years, especially in situ phenotyping and studies in mutant and transgenic mice, has reliably identified these cells as members of the natural killer (NK) cell lineage, and they are referred to here as granulated uterine NK (uNK) cells. Much of the evidence is reviewed here, along with a description of the spatial and temporal aspects of the differentiation of these cells. Especially highlighted are their life history and their likely importance early in pregnancy before development of the metrial gland proper. Their relation to other NK cell populations, especially activated cells, as well as their possible functions during pregnancy, are discussed. Because these cells develop in the unique microenvironment of the pregnant uterus and appear to differentiate along a specific pathway, hypotheses are proposed regarding the regulation of granulated uNK cell differentiation in this site.