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Published online 10 May 2004 doi:10.1084/jem.20032206
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 10, 1331-1341
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DNAM-1 and PVR Regulate Monocyte Migration through Endothelial Junctions

Nicolas Reymond1, Anne-Marie Imbert2, Elisabeth Devilard3, Stéphanie Fabre1, Christian Chabannon2, Luc Xerri3, Catherine Farnarier4, Claudia Cantoni5,6, Cristina Bottino5, Alessandro Moretta6, Patrice Dubreuil1, and Marc Lopez1

1 Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 599, Institut de Cancérologie de Marseille, 13009 Marseille, France
2 Centre de Thérapie Cellulaire et Génique and 3 Laboratoire de Biopathologie, Institut Paoli-Calmettes, 13273 Marseille Cedex 9, France
4 Laboratoire d'Immunologie, INSERM U.600, Hôpital de Sainte-Marguerite, 13274 Marseille Cedex 9, France
5 Istituto Giannina Gaslini, 16148 Genova, Italy
6 Dipartimento di Medicina Sperimentale, Università di Genova, 16132 Genova, Italy

Address correspondence to Marc Lopez, Institut National de la Santé et de la Recherche Médicale UMR599, Institut de Cancérologie de Marseille, IFR 137, 27 Bd. Lei-Roure, 13009 Marseille, France. Phone: 33-491-75-84-17; Fax: 33-491-26-03-64; email: lopez{at}marseille.inserm.fr

DNAX accessory molecule 1 (DNAM-1; CD226) is a transmembrane glycoprotein involved in T cell and natural killer (NK) cell cytotoxicity. We demonstrated recently that DNAM-1 triggers NK cell–mediated killing of tumor cells upon engagement by its two ligands, poliovirus receptor (PVR; CD155) and Nectin-2 (CD112). In the present paper, we show that PVR and Nectin-2 are expressed at cell junctions on primary vascular endothelial cells. Moreover, the specific binding of a soluble DNAM-1–Fc molecule was detected at endothelial junctions. This binding was almost completely abrogated by anti-PVR monoclonal antibodies (mAbs), but not modified by anti–Nectin-2 mAbs, which demonstrates that PVR is the major DNAM-1 ligand on endothelial cells. Because DNAM-1 is highly expressed on leukocytes, we investigated the role of the DNAM-1–PVR interaction during the monocyte transendothelial migration process. In vitro, both anti–DNAM-1 and anti-PVR mAbs strongly blocked the transmigration of monocytes through the endothelium. Moreover, after anti–DNAM-1 or anti-PVR mAb treatment, monocytes were arrested at the apical surface of the endothelium over intercellular junctions, which strongly suggests that the DNAM-1–PVR interaction occurs during the diapedesis step. Altogether, our results demonstrate that DNAM-1 regulates monocyte extravasation via its interaction with PVR expressed at endothelial junctions on normal cells.

Key Words: CD226 • CD155 • Nectin • endothelium • diapedesis

Abbreviations used in this paper: AJ, adherens junction; DNAM-1, DNAX accessory molecule-1; HUVEC, human umbilical vein endothelial cell; JAM, junctional adhesion molecule; PECAM-1, platelet–endothelial cell adhesion molecule 1; PVR, poliovirus receptor; TEM, transendothelial migration.


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