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The Journal of Immunology, 2007, 179, 3804-3811
Copyright © 2007 by The American Association of Immunologists, Inc.
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The B7 Homolog Butyrophilin BTN2A1 Is a Novel Ligand for DC-SIGN1

Georg Malcherek2, Luzia Mayr3, Pedro Roda-Navarro4, David Rhodes, Nigel Miller and John Trowsdale

Department of Pathology, Division of Immunology, University of Cambridge, Cambridge, United Kingdom

The MHC-encoded butyrophilin, BTN2A1, is a cell surface glycoprotein related to the extended family of B7 costimulatory molecules. BTN2A1 mRNA was expressed in most human tissues, but protein expression was significantly lower in leukocytes. An Ig-fusion protein of BTN2A1 bound to immature monocyte-derived dendritic cells. Binding diminished upon MoDC maturation and no binding was detected to Langerhans cells. Induction of the counterreceptor was IL-4 dependent and occurred early during dendritic cell differentiation. The interaction required the presence of Ca2+ and was mediated by high-mannose oligosaccharides. These properties matched DC-SIGN, a DC-specific HIV-1 entry receptor. This was confirmed by binding of soluble BTN2A1 to DC-SIGN-transfectants and its inhibition by a specific Ab. DC-SIGN bound to native BTN2A1 expressed on a range of tissues. However, BTN2A1 was not recognized on some normal cells such as HUVECs despite a similar expression level. The BTN2A1 of tumor cells such as HEK293T have more high-mannose moieties in comparison to HUVECs, and those high-mannose moieties are instrumental for binding to DC-SIGN. The data are consistent with tumor- or tissue-specific glycosylation of BTN2A1 governing recognition by DC-SIGN on immature monocyte-derived dendritic cells.

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 the Wellcome Trust.

2 Address correspondence and reprint requests to Dr. Georg Malcherek, Department of Pathology, Division of Immunology, Tennis Court Road, Cambridge, U.K. E-mail address: gfjm2{at}cam.ac.uk

3 Current address: Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge, U.K.

4 Current address: Max Planck Institute for Molecular Physiology, Department of System Cell Biology, Otto-Hahn-Str. 11, Dortmund, Germany

5 Abbreviations used in this paper: BTN, butyrophilins; BTNL2, butyrophilin-like 2; DC, dendritic cell; DC-SIGN, DC-specific ICAM-3 grabbing nonintegrin; CEA, carcinoembryonic Ag; MoDC, monocyte-derived DCs; LC, Langerhans cells; GNA, Galanthus nivalis agglutinin; IHC, immunohistochemistry; imMoDC, immature MoDCs; Endo H, Endoglycosidase H; TRIM, tripartite motif; CI, calcium ionophore; HFF, human foreskin fibroblasts.






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