The Journal of Experimental Medicine
ThymUS '08
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Published online 11 October 2004 doi:10.1084/jem.20040583
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 1075-1081
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Brief Definitive Report

 The Cytomegalovirus m155 Gene Product Subverts Natural Killer Cell Antiviral Protection by Disruption of H60–NKG2D Interactions

Melissa B. Lodoen1, Gerardo Abenes2, Sean Umamoto2, Jeffrey P. Houchins3, Fenyong Liu2, and Lewis L. Lanier1

1 Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143
2 Division of Infectious Diseases, School of Public Health, University of California, Berkeley, Berkeley, CA 94720
3 R&D Systems, Minneapolis, MN 55413

Address correspondence to Lewis L. Lanier, Dept. of Microbiology and Immunology, Box 0414, University of California, San Francisco, San Francisco, CA 94143. Phone: (415) 514-0829; Fax: (415) 502-8424; email: lanier{at}itsa.ucsf.edu

Natural killer (NK) cells are an important early mediator of host immunity to murine cytomegalovirus (MCMV) infection. However, MCMV has evolved mechanisms to elude recognition and clearance by NK cells. We have identified an MCMV immune evasion protein that impairs NKG2D-mediated NK cell antiviral activity. Infection of BALB/c 3T3 cells with the Smith strain of MCMV resulted in strong down-regulation of H60, a high affinity ligand for NKG2D, from the surface of virus-infected cells. The MCMV m155 protein specifically down-regulated H60 without affecting expression of the other known NKG2D ligands, RAE-1 and MULT-1. Treatment with the proteasome inhibitors lactacystin or epoxomicin reversed m155 down-regulation of H60. An MCMV mutant virus lacking m155 was severely attenuated in BALB/c mice; however, treatment with neutralizing anti-NKG2D monoclonal antibody or with NK-depleting anti-asialo GM1 antisera restored virulence of the mutant virus. Thus, down-regulation of H60 by m155 is a powerful mechanism of inhibiting NKG2D-mediated antiviral function.

Key Words: NKG2D • H60 • cytomegalovirus • NK cell


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