The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions.
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.
Department of Microbiology and Immunology, Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Melissa B
MB
Lodoen
Gerardo
G
Abenes
Sean
S
Umamoto
Jeffrey P
JP
Houchins
Fenyong
F
Liu
Lewis L
LL
Lanier
D000818:Animals; D041702:BALB 3T3 Cells; D002352:Carrier Proteins / Q000235:genetics; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D018146:Muromegalovirus / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins / Q000502:physiology*
D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; C491219:Raet1a protein, mouse; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C468260:UL16 binding protein 1, mouse; D014764:Viral Proteins; C104783:m152 protein, cytomegalovirus; C114735:minor H antigen H60; D046988:Proteasome Endopeptidase Complex