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. 2006 Aug 7;203(8):1843-50.
doi: 10.1084/jem.20060514. Epub 2006 Jul 10.

The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60

Tihana Lenac  1 , Matthias Budt, Jurica Arapovic, Milena Hasan, Albert Zimmermann, Hrvoje Simic, Astrid Krmpotic, Martin Messerle, Zsolt Ruzsics, Ulrich H Koszinowski, Hartmut Hengel, Stipan Jonjic
Affiliations

The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60

Tihana Lenac et al. J Exp Med. .

Abstract

Members of the alpha- and beta-subfamily of herpesviridae encode glycoproteins that specifically bind to the Fc part of immunoglobulin (Ig)G. Plasma membrane resident herpesviral Fc receptors seem to prevent virus-specific IgG from activating antibody-dependent effector functions. We show that the mouse cytomegalovirus (MCMV) molecule fcr-1 promotes a rapid down-regulation of NKG2D ligands murine UL16-binding protein like transcript (MULT)-1 and H60 from the cell surface. Deletion of the m138/fcr-1 gene from the MCMV genome attenuates viral replication to natural killer (NK) cell response in an NKG2D-dependent manner in vivo. A distinct N-terminal module within the fcr-1 ectodomain in conjunction with the fcr-1 transmembrane domain was required to dispose MULT-1 to degradation in lysosomes. In contrast, down-modulation of H60 required the complete fcr-1 ectodomain, implying independent modes of fcr-1 interaction with the NKG2D ligands. The results establish a novel viral strategy for down-modulating NK cell responses and highlight the impressive diversity of Fc receptor functions.

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Figures

Figure 1.
Figure 1.
Selective down-modulation of NKG2D ligands MULT-1 and H60 by MCMV fcr-1. 12 h p.i., NIH3T3 cells were analyzed for the expression of NKG2D ligands using the NKG2D-PE tetramer (a), whereas SVEC4-10 cells were stained for the expression of MULT-1 with rat anti–MULT-1 mAb (b) or with F(ab)2 fragments of rat anti–MULT-1 mAb (c) followed by anti–rat-PE. H60-3T3 cells were stained 16 h p.i. with rat anti-H60 mAb followed by anti–rat-FITC (d). 12 h p.i. B12 cells were stained with anti-RAE–1αβγ mAb (e) or anti–H-2Kd mAb (f) followed by FITC-labeled secondary Ab. Irrelevant primary mAbs were used as a negative control (thin line). Infection was performed with 1 PFU per cell of indicated viruses.
Figure 2.
Figure 2.
fcr-1 is efficient both in vivo and in isolated in vitro conditions. (a) CV-1 cells infected with indicated Vaccinia viruses for 16 h or (b) HEK 293T cells cotransfected with indicated plasmids for 24 h were analyzed for the expression of MULT-1 or H60. Irrelevant primary mAbs were used as a negative control (thin line). NK cell–depleted or undepleted BALB/c mice were injected i.v. with (c) 2 × 105 PFU of indicated viruses or (d) 104 BALB/c MEF cells were infected for 12 h with 2 PFU of indicated viruses. (e) Untreated BALB/c mice or mice treated with anti-NKG2D mAb were i.v. injected with 2 × 105 PFU of indicated viruses. Titers in the lungs of individual mice (circles) 3 d p.i. and median values (horizontal bars) are shown. The differences between the groups of untreated mice infected with Δm138/fcr-1 and WT or m138/fcr-1 revertant virus were significant (P < 0.005). Depletion of NK cells and blockade of NKG2D resulted in a significant increase (P < 0.005 for c and d; P < 0.025 for e) of Δm138/fcr-1 virus titers.
Figure 3.
Figure 3.
The fcr-1 Ig1 domain is responsible for MULT-1 down-modulation. SVEC4-10 cells infected for 22 h with 5 PFU per cell of indicated viruses or left uninfected were stained with rat anti–MULT-1 mAb or anti-H60 mAb. Irrelevant primary antibody was used as a negative control (thin line).
Figure 4.
Figure 4.
fcr-1 is readily detected on the cell surface of MCMV-infected cells and surface resident MULT-1 is rapidly recycling. (a) (10)1 cells were mock infected or infected with 5 PFU per cell of WT MCMV or Δm138/fcr-1. 15 h p.i., the cells were surface stained and intracellularly stained with mouse IgG Fc fragment and Cy5-labeled anti–mouse IgG. (b) Confocal analysis was performed on MULT-1–3T3 cells Ab-tagged for surface MULT-1 (red) as described for the uptake assay. Transferrin-FITC (green) was added in parallel with anti–MULT-1 mAb.
Figure 5.
Figure 5.
fcr-1 targets surface resident MULT-1 for lysosomal degradation. SVEC4-10 (a and c) or MULT-1–3T3 (b) cells either mock infected or infected with 4 PFU per cell of WT MCMV or Δm138/fcr-1 were Ab-tagged for surface proteins. Cells were treated as described for uptake assay with rat anti–MULT-1 mAb (IgG2a). In addition, F(ab)2fragments of anti–MULT-1 mAb or rat anti-CD29 mAb (IgG2a) were used (c). After incubation for the indicated time periods, the cells were analyzed for the surface proteins (a and c). MULT-1 expression was examined after treatment with different inhibitors as described in the confocal microscopy section (b).
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