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Coordinate Regulation of Lymphocyte-Endothelial Interactions by Pregnancy-Associated Hormones ¹

Sirirak Chantakru^2,*, Wan-Chao Wang, Marianne van den Heuvel^*, Siamak Bashar^*, Amanda Simpson^*, Qing Chen, B. Anne Croy^* and Sharon S. Evans^3,

^* Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada; and Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

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 ₄ integrin-dependent adhesion pathways for circulating human CD56^bright 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 17-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 ₄₇ 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 17-estradiol and/or progesterone replacement therapy. Adhesion of human CD56^bright cells to uteri from pregnant or hormone-treated ovariectomized mice was enhanced through L-selectin- and ₄ 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 CD56^bright 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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