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The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions.

Lodoen MB, Abenes G, Umamoto S, Houchins JP, Liu F, Lanier LL - J. Exp. Med. (2004)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
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.

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MCMV infection down-regulates H60. 3T3 cells were infected with wild-type MCMV (Smith), DMS94.5 (Δm150-165), or ΔMC96.24 (Δm152) viruses at an MOI of 2. 48 h after infection, cells were stained with control IgG2a (dotted histograms) or anti-H60 mAb (bold histograms).
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fig1: MCMV infection down-regulates H60. 3T3 cells were infected with wild-type MCMV (Smith), DMS94.5 (Δm150-165), or ΔMC96.24 (Δm152) viruses at an MOI of 2. 48 h after infection, cells were stained with control IgG2a (dotted histograms) or anti-H60 mAb (bold histograms).

Mentions: Infection of 3T3 cells with MCMV results in strong down-regulation of RAE-1 by gp40 encoded by the m152 gene (12, 13). However, gp40 did not down-regulate H60, another high affinity ligand for NKG2D. To address whether MCMV affects H60, we infected 3T3 cells, which constitutively express H60 on the cell surface, with MCMV. 48 h after infection, we analyzed cells for H60. We observed a marked decrease in the level of cell surface H60 after infection (Fig. 1).


The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions.

Lodoen MB, Abenes G, Umamoto S, Houchins JP, Liu F, Lanier LL - J. Exp. Med. (2004)

MCMV infection down-regulates H60. 3T3 cells were infected with wild-type MCMV (Smith), DMS94.5 (Δm150-165), or ΔMC96.24 (Δm152) viruses at an MOI of 2. 48 h after infection, cells were stained with control IgG2a (dotted histograms) or anti-H60 mAb (bold histograms).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211837&req=5

fig1: MCMV infection down-regulates H60. 3T3 cells were infected with wild-type MCMV (Smith), DMS94.5 (Δm150-165), or ΔMC96.24 (Δm152) viruses at an MOI of 2. 48 h after infection, cells were stained with control IgG2a (dotted histograms) or anti-H60 mAb (bold histograms).
Mentions: Infection of 3T3 cells with MCMV results in strong down-regulation of RAE-1 by gp40 encoded by the m152 gene (12, 13). However, gp40 did not down-regulate H60, another high affinity ligand for NKG2D. To address whether MCMV affects H60, we infected 3T3 cells, which constitutively express H60 on the cell surface, with MCMV. 48 h after infection, we analyzed cells for H60. We observed a marked decrease in the level of cell surface H60 after infection (Fig. 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus