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Killer Ig-Like Receptor Expression in Uterine NK Cells Is Biased toward Recognition of HLA-C and Alters with Gestational Age¹

Andrew M. Sharkey^*, Lucy Gardner^*, Susan Hiby^*, Lydia Farrell^*, Richard Apps^*, Leanne Masters^*, Jodie Goodridge, Louise Lathbury, C. Andrew Stewart^2,, Sanjay Verma^* and Ashley Moffett^3,*

^* Department of Pathology, University of Cambridge, Cambridge, United Kingdom; Department of Clinical Immunology and Biochemical Genetics, PathWest, Royal Perth Hospital, Perth, Western Australia, Australia; Department of Surgery and Pathology, University of Western Australia, Perth, Western Australia, Australia; and Centre d’Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France

Immunogenetic studies suggest that interactions between maternal killer Ig-like receptor (KIR) expressed by uterine NK (uNK) cells, and fetal HLA-C molecules on trophoblast, influence the success of human placentation. However, the exact functional response of fresh uNK cells to trophoblast HLA-C molecules is unknown. In this study, we show by quantitative RT-PCR and FACS that both activating and inhibitory KIR specific for HLA-C are expressed at higher levels and on an increased proportion of NK cells in the human decidua compared with blood. In contrast, expression of KIR3DL1/S1, which is specific for HLA-B, is similar in both NK cell populations. Remarkably, there is also a temporal change in the expression pattern of HLA-C-specific KIR, with a decline in both intensity of expression and frequency on uNK cells throughout the first trimester of pregnancy. This selective up-regulation of KIR has functional consequences because uNK cells show increased binding of HLA-C tetramers compared with blood NK cells. Ab cross-linking shows that these KIR are functional and results in increased cytokine secretion. uNK cells, therefore, exhibit a unique KIR profile that enhances their ability to recognize trophoblast cells expressing HLA-C at the materno-fetal interface. This is the first report to demonstrate selective regulation of KIR expression over time in vivo in a normal physiological situation and suggests that KIR expression by uNK cells is regulated by the tissue microenvironment in the decidua.

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 Wellcome Trust Grants GR076856 and GR079304.

² Current address: National Cancer Institute, Building 567 Room 206, P.O. Box B, Frederick, MD 21702.

³ Address correspondence and reprint requests to Dr. A. Moffett, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, U.K. E-mail address: am485{at}cam.ac.uk

⁴ Abbreviations used in this paper: uNK, uterine NK cell; KIR, killer Ig-like receptor; pbNK, peripheral blood NK cell; VEGF, vascular endothelial growth factor.