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Vascular Endothelial Growth Factor C Facilitates Immune Tolerance and Endovascular Activity of Human Uterine NK Cells at the Maternal-Fetal Interface¹

Satyan S. Kalkunte^*, Teddy F. Mselle, Wendy E. Norris^*, Charles R. Wira, Charles L. Sentman and Surendra Sharma^2,*

^* Department of Pediatrics, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, RI 02905; Department of Microbiology & Immunology and Department of Physiology, Dartmouth Medical School, Hanover, NH 03755

Although replete with cytotoxic machinery, uterine NK (uNK) cells remain tolerant at the maternal-fetal interface. The mechanisms that facilitate the uNK cell tolerance are largely unknown. In this study, we demonstrate that vascular endothelial growth factor (VEGF) C, a proangiogenic factor produced by uNK cells, is responsible for their noncytotoxic activity. VEGF C-producing uNK cells support endovascular processes as demonstrated in a three-dimensional coculture model of capillary tube formation on Matrigel. Peripheral blood NK cells fail to produce VEGF C and remain cytotoxic. This response can be reversed by exogenous VEGF C. We show that cytoprotection by VEGF C can be related to induction of the TAP-1 expression and MHC class I assembly in target cells. Small interfering RNA-mediated silencing of TAP-1 expression abolished the VEGF C-imparted protection. Overall, these results demonstrate that empowerment of uNK cells with angiogenic factors keeps them noncytotoxic. This phenotype is critical to their pregnancy-compatible immunovascular role during placentation and fetal development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Institutes of Health and National Institute on Environmental Sciences, P20RR018728, and Superfund Basic Research Program Award (P42ES013660), National Institutes of Health Grant AI51877, and Fogarty International Center Grant FIC 2D43TW006807.

² Address correspondence and reprint requests to Dr. Surendra Sharma, Department of Pediatrics, Women and Infants Hospital, 101 Dudley Street, Providence, RI 02905. E-mail address: ssharma{at}wihri.org

³ Abbreviations used in this paper: uNK, uterine NK; HUtEC, human uterine endothelial cell; pNK, peripheral blood NK; dNK, decidual NK; VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; NCR, natural cytotoxicity receptor; NPS, normal pregnancy serum; siRNA, small interfering RNA.

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