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Viral Interference with B7-1 Costimulation: A New Role for Murine Cytomegalovirus Fc Receptor-1¹

Justine D. Mintern^*, Elizabeth J. Klemm^*, Markus Wagner^*, Marie Eve Paquet^*, Melanie D. Napier^*, You Me Kim^*, Ulrich H. Koszinowski and Hidde L. Ploegh^2,*

^* Department of Pathology, Harvard Medical School, Boston, MA 02115; and Max von Pettenkofer Institut, Ludwig-Maximilians-Universität München, Munich, Germany

Murine CMV (MCMV), a -herpesvirus, infects dendritic cells (DC) and impairs their function. The underlying events are poorly described. In this study, we identify MCMV m138 as the viral gene responsible for promoting the rapid disappearance of the costimulatory molecule B7-1 (CD80) from the cell surface of DC. This was unexpected, as m138 was previously identified as fcr-1, a putative virus-encoded FcR. m138 impaired the ability of DC to activate CD8⁺ T cells. Biochemical analysis and immunocytochemistry showed that m138 targets B7-1 in the secretory pathway and reroutes it to lysosomal associated membrane glycoprotein-1⁺ compartments. These results show a novel function for m138 in MCMV infection and identify the first viral protein to target B7-1.

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 J.D.M. was supported by a CJ Martin Fellowship. M.W. was supported by a Longterm Fellowship from the Human Frontiers Science Organization. Y.M.K. was supported by a Leukemia & Lymphoma Society Fellowship. M.E.P. was funded by Fonds de la Recherche en Sante du Quebec.

² Address correspondence and reprint requests to Dr. Hidde L. Ploegh, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142-1479. E-mail address: ploegh{at}wi.mit.edu

³ Abbreviations used in this paper: MCMV, murine CMV; DC, dendritic cell; BMDC, bone marrow-derived DC; CHO, Chinese hamster ovary; DC2, D2SC/1 DC; EEA-1, early endosomal Ag-1; Endo H, endoglycosidase H; ER, endoplasmic reticulum; HA, hemagglutinin; ICOSL, inducible costimulatory molecule ligand; KSHV, Kaposi’s sarcoma-associated herpesvirus; LAMP-1, lysosomal-associated membrane glycoprotein-1; MOI, multiplicity of infection; PD-L, programmed death ligand; PDI, protein disulfide isomerase; Tfn, transferrin.

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