Coordinate Regulation of Lymphocyte-Endothelial Interactions by Pregnancy-Associated Hormones

Abstract

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.

Human First-Trimester Trophoblast Cells Recruit CD56brightCD16− NK Cells into Decidua by Way of Expressing and Secreting of CXCL12/Stromal Cell-Derived Factor 1

“…Although Peripheral CD16 ϩ NK cells also express CXCR4, as reported by Campbell et al (26), the intensity of CXCR4 on the peripheral CD16 ϩ and CD16 Ϫ NK cell surface, and the ability of these two NK cell subsets to migrate in response to CXCL12 are very likely different. More important, in humans circulating CD56 bright CD16 Ϫ NK cells express functionally active L-selectin at extremely high levels, compared with CD56 dim CD16 ϩ NK cells (33), and L-selectin is necessary in the adhesion of CD56 bright CD16 Ϫ NK cells to the decidualizing uterus (12,34 This report has demonstrated that trophoblast cells contribute to the recruitment of the decidual CD56 bright CD16 Ϫ NK cells. It should be noted that many adhesion molecules are expressed in uterine stroma and uterine stroma itself is capable of attracting circulating leukocytes, as distinct populations of immune cells migrate into the uterus during the course of the menstrual cycle (5,35).…”

Role of the N, N′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

“…Both the fact that the T cell population from axillar nodes was not affected during DHEA-induced hyperandrogenization and that the T cell population from retroperitoneal lymph nodes was affected -and also the fact that hyperandrogenization induced a similar T cell population when samples from retroperitoneal lymph tissue were compared with those obtained from ovarian tissue -lead us to suggest that the local inflammatory status would be contributing to a selective differentiation of T cells. According to this hypothesis, lymph nodes and sex steroids are related to different systems, thus suggesting a coordinated organ-specific and steroid hormone relationship (Chantakru et al 2003). Moreover, the E receptor expressed by follicular dendritic cells in lymph nodes has recently been proposed as a novel pathological marker (Sapino et al 2003) and the deficiency of E caused by ovariectomy or menopause is involved in the T lymphocyte status (Safadi et al 2000).…”

NK Cells Detect Changes in Adaptive Immunity within Mouse Decidua from Gestation Day Eight

“…Further, NK cells from the same blood adhered to gd6-7 tissue as single cells but adhered in progressively larger clusters to sections from tissues of more advanced gestational ages [16]. These clusters did not adhere over the fetus or placenta but were found broadly across the decidua basalis, suggesting that a major functional change within the decidua basalis was being detected by the blood indicator lymphocytes.…”

“…Throughout our studies employing mouse decidua as an adhesion substrate, we noted that use of sections from more advanced pregnancies (gd 8-12) led to huge gains in numbers of adherent NK cells from a common blood sample, even when analysed on a single slide [16].…”