Uterine NK (uNK) cells are abundant in human and murine uteri during decidualization. It is unclear whether precursors of uNK (pre-uNK) cells self-renew or are recruited from other sites. To assess self-renewal of pre-uNK cells, uterine segments from NK cell-competent mice were grafted orthotopically into NK/uNK cell-deficient or wild-type mice. Only in wild-type recipients did decidualized grafts contain uNK cells, indicating that pre-uNK cells do not self-renew in uterus. To identify pre-uNK cell sources, thymus, bone marrow, lymph node, or spleen cells were grafted from virgin or pregnant NK cell-competent donors into mated NK/uNK cell-deficient recipients. Cells from secondary lymphoid tissues of pregnant donors gave high level uNK cell reconstitution, which was independent of chemokine receptors CCR2 or CCR5. Pregnancy-induced changes to lymphocyte-endothelial cell interactions were documented using adhesion of human lymphocytes to frozen mouse tissue sections under shear. A dynamic increase was observed in L-selectin- and α4 integrin-dependent adhesion of CD56bright NK cells to decidualizing uterus and in human PBL adhesion to lymph node endothelium. These data support a model that attributes the dramatic increases in human and murine uNK cells during decidualization to precursor cell recruitment.

In primates, including women, and in rodents, natural killer lymphocytes (NK cells) have a unique relationship with the decidualizing uterus. Implantation sites from genetically modified and transplanted mice have proven useful models for understanding potential mechanisms involved in the recruitment, activation and functions of human CD56(bright) uterine (u)NK cells. Key findings are reviewed in this article. In mice, uNK precursor cells are recruited from secondary lymphoid tissues and are activated coincident with their uterine arrival. uNK cells proliferate, produce cytokines (interferon gamma (IFN-gamma) and interleukin 18 (IL-18) and IL-27), and terminally differentiate into granulated lymphocytes. Many uNK cells proliferate within the myometrium at each implantation site forming a structure, the mesometrial lymphoid aggregate of pregnancy (MLAp) that surrounds blood vessels servicing each placenta. Post-mitotic uNK cells are abundant within decidua basalis; frequently (<25%) associating with spiral arteries, intramurally and intraluminally. From mid-gestation, numbers of uNK cells decline. Studies of implantation sites in mice lacking uNK cells, IFN-gamma, components of IFN-gamma-induction and -signalling pathways or IFN-gamma-regulated genes indicate that uNK cell-derived IFN-gamma is essential in triggering pregnancy-induced spiral artery modification. Decidual maintenance and uNK cell death are additional effects of uNK cell-derived IFN-gamma. Thus, during the first half of gestation, uNK cells contribute to and sustain important changes in the maternal placental bed.

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Precursors of uterine NK cells home to the uterus during early pregnancy from multiple lymphohemopoietic sources. In mouse uterine tissue, pregnancy markedly up-regulates both L-selectin- and α4 integrin-dependent adhesion pathways for circulating human CD56bright cells, the phenotype of human uterine NK cells. Based on roles for these adhesion molecules in lymphocyte homing, we examined effects of pregnancy or the steroid hormones 17β-estradiol or progesterone on lymphocyte-endothelial interactions in secondary lymphoid tissues and in uterus. From preimplantation gestation day 3, specialized high endothelial venules in peripheral lymph nodes and Peyer’s patches supported elevated L-selectin and α4β7 integrin-dependent lymphocyte adhesion under shear throughout pregnancy, as compared with high endothelial venules of virgin or postpartum donors. Squamous endothelium from nonlymphoid tissue was not affected. Pregnancy-equivalent endothelial responses were observed in lymph nodes and Peyer’s patches from ovariectomized mice receiving 17β-estradiol and/or progesterone replacement therapy. Adhesion of human CD56bright cells to uteri from pregnant or hormone-treated ovariectomized mice was enhanced through L-selectin- and α4 integrin-dependent mechanisms and involved multiple vascular adhesion molecules including mucosal addressin cell adhesion molecule-1, VCAM-1, and peripheral lymph node addressin. Analysis of Tie2-green fluorescence protein transgenic mice demonstrated that CD56bright cells adhered primarily to vascular endothelium within the decidua basalis. Microdomain localization of adhesion involving large clusters of lymphocytes was induced on uteri from natural matings, but not pseudopregnancy. Steroid hormones also had independent effects on L-selectin function in splenic lymphocytes that mimicked physiological stimulation induced by pregnancy or fever-range temperatures. These results provide the first evidence for coordinated, organ-specific, steroid hormone-induced changes in lymphocyte homing mechanisms that could contribute to local and systemic immune responses during pregnancy.

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