Assessment of Requirements for IL-15 and IFN Regulatory Factors in Uterine NK Cell Differentiation and Function During Pregnancy

Abstract

In mouse and human, precursors of NK cell lineage home to decidualizing uteri. To assess the requirement for IL-15, an essential cytokine for NK differentiation in lymphoid tissue, on uterine NK (uNK) cell differentiation, implantation sites from IL-15−/− mice were analyzed histologically. IL-15−/− implantation sites had no uNK cells, no spiral-artery modification, and lacked the decidual integrity found in normal mice. IL-15−/− recipients of C57BL/6 marrow displayed similar pathology. However, implantation sites from recombination-activating gene-2−/−γc−/− (alymphoid) recipients of IL-15−/− marrow showed normal uNK cells, modified spiral arteries, and well-developed decidua basalis. Deletion of the IFN-regulatory factor (IRF)-1, but not IRF-2 (factors important in peripheral NK cell differentiation) limited but did not prevent uNK cell development. In situ hybridization localized IRF-1 largely to placental trophoblast cells. IRF-1−/− marrow transplanted into recombination-activating gene-2−/−γc−/− displayed competence for full uNK cell differentiation. IL-15 mRNA expression at implantation sites of IRF-1−/− and C57BL/6 was similar, suggesting that, unlike in bone marrow and spleen, IRF-1 does not regulate IL-15 in the pregnant uterus. Terminal differentiation of uNK cells was not promoted in pregnant IRF-1−/− mice by 5-day infusion of murine rIL-15, suggesting that IRF-1 deficiency rather than IL-15 deficiency limits uNK cell differentiation in these mice. Further, IRF-1 regulates placental growth, birth weight, and postnatal growth of offspring. These studies indicate that uNK cell development and maturation share some aspects with NK cell development in other tissues, but also display distinctive tissue-specific regulation.

Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling

“…7). One explanation for the activated-like phenotype of the decidual NK subset can be inferred from the chronic intimate interaction of these cells with semiallogeneic extravillous trophoblasts that invade maternal decidua and the cytokine-enriched local microenvironment (7,64). Such conditions might induce, at least, a partial activation state on NK cells found in the decidua.…”

“…This subset has long been subject to extensive research efforts, as it is hypothesized that the abundance of these cells inside the decidua is related to induction of maternal immune tolerance toward the semiallogeneic fetus (64). Koopman et al (65) have recently conducted a comparative genomic analysis between human decidual and peripheral NK subsets, showing that decidual NK cells are unique cells that differ notably from peripheral blood-derived NK cells.…”

Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice

“…4A). Spiral arterial wall-to-lumen diameter ratios for normoglycemic NOD mice and NOD-.scid mice were greater than reported for B6 mice (34). This may indicate a basal arterial defect in the NOD strain.…”

Genetic Deletion of Placenta Growth Factor in Mice Alters Uterine NK Cells

“…This effect was not observed. Small PL were found but spiral arterial modification was only slightly delayed in PlGF null mice, not prevented as in uNK cell-deficient mice (42). Whether the pathology seen in implantation sites of PlGF null mice could be reversed by VEGF rather than PlGF treatment is a question that, when answered, may shed light on whether VEGF therapy of women at risk for pre-eclampsia will be successful.…”