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Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus

Abstract

Human cytomegalovirus, a chief pathogen in immunocompromised people, can persist in a healthy immunocompetent host throughout life without being eliminated by the immune system. Here we show that pp65, the main tegument protein of human cytomegalovirus, inhibited natural killer cell cytotoxicity by an interaction with the activating receptor NKp30. This interaction was direct and specific, leading to dissociation of the linked CD3ζ from NKp30 and, consequently, to reduced killing. Thus, pp65 is a ligand for the NKp30 receptor and demonstrates a unique mechanism by which an intracellular viral protein causes general suppression of natural killer cell cytotoxicity by specific interaction with an activating receptor.

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Figure 1: NKp30-Ig interacts with pp65 in infected cells.
Figure 2: Direct interaction between viral pp65 and NKp30.
Figure 3: Kinetics of interactions of pp65 and NKp30-Ig.
Figure 4: Expression of pp65 inhibits NK cell activity.
Figure 5: Direct inhibition mediated by pp65.
Figure 6: NK cell cytotoxicity is generally reduced by pp65.
Figure 7: Interaction with pp65 causes dissociation of the CD3ζ chain from NKp30 on NK cells.
Figure 8: Expression of pp65 on cell surfaces inhibits NK cell cytotoxicity.

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Acknowledgements

We thank E. Vivier, H. Hengel and M. Lopez-Botet for suggestions; and D. Davis and D. Coen for critically reading the manuscript. Supported by the Israel Science Foundation (O.M. and D.W.), European Commission (QLK2-CT-2002-011112 to O.M.), Hadassah Women's Health Research Foundation (D.W.) and Deutsche Forschungsgemeimschaft (SFB490 to B.P.).

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Correspondence to Ofer Mandelboim.

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Supplementary information

Supplementary Fig. 1

NKp30-Ig immunoprecipitates HCMV pp65 protein. (PDF 1140 kb)

Supplementary Fig. 2

pp65 blocks the binding of an anti-NKp30 mAb to the NKp30 receptor in a dose dependent manner. (PDF 739 kb)

Supplementary Fig. 3

Reagent specificity. (PDF 1044 kb)

Supplementary Fig. 4

The anti-pp65 mAb does not abolish pp65-mediated inhibition. (PDF 755 kb)

Supplementary Table 1

Expression of inhibitory and activating receptors by NK clones (PDF 1373 kb)

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Arnon, T., Achdout, H., Levi, O. et al. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol 6, 515–523 (2005). https://doi.org/10.1038/ni1190

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