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Endometrial NK Cells Are Special Immature Cells That Await Pregnancy¹

Irit Manaster^*, Saar Mizrahi^*, Debra Goldman-Wohl, Hen Y. Sela, Noam Stern-Ginossar^*, Dikla Lankry^*, Raizy Gruda^*, Arye Hurwitz, Yuval Bdolah, Ronit Haimov-Kochman, Simcha Yagel and Ofer Mandelboim^2,*

^* Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, BioMedical Research Institute, Jerusalem, Israel; Department of Obstetrics and Gynecology, Hadassah University Hospital-Mount Scopus, Jerusalem, Israel; and Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.

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 by grants from the U.S.-Israel Bi-national Science Foundation, the Israeli Cancer Research Foundation, The Israeli Science Foundation, The Rosetrees Trust, The European Consortium (MRTN-CT-2005 and LSCH-CT-2005-518178) and by the Association for International Cancer Research (all to O.M). O.M is The Edward Crown professor of General and Tumor Immunology. S.Y. is supported by the Women’s Health Fund and the Office of the Chief Scientist Ministry of Health.

² Address correspondence and reprint requests to Dr. Ofer Mandelboim, Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel. E-mail address: oferm{at}ekmd.huji.ac.il

³ Abbreviations used in this paper: eNK, endometrium NK cell; dNK, decidual NK cell; NCRs, natural cytotoxicity receptor; IVF, in vitro fertilization; pb, peripheral blood; VEGF, vascular endothelial growth factor; PLGF, placental growth factor; MICA, MHC class I chain-related chain A; MICB, MHC class I chain-related chain B; ULBP, UL-16 binding protein.