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Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells

Abstract

Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation1. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface2,3,4,5,6,7,8. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined9,10,11,12,13,14. NKp46 is thought to be the main activating receptor for human NK cells9,15. Here we show that a soluble NKp46–immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin–neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein.

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Figure 1: Lysis of HN-transfected 293T cells by NK GAL.
Figure 2: Lysis of IV-infected 1106mel cells by NK GAL and derived clones.
Figure 3: NKp46 binding to and activation by haemagglutinin.

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Acknowledgements

We thank N. P. Restifo for the 1106mel cells; A. Portner from St. Jude Children's Research Hospital for providing the pca-svhn plasmid; and J. Skehel and R. Gonsalves from National Institute of Medical Research for the purified HA. O.M. is supported by the Israel Science Foundation and The Charles H. Revson Foundation. A.P. is supported by the Israel Science Foundation and by the USA–Israel Binational Science Foundation. O.M. and A.P. are supported by the Israel Cancer Research Foundation.

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Correspondence to Angel Porgador.

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Mandelboim, O., Lieberman, N., Lev, M. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060 (2001). https://doi.org/10.1038/35059110

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