The human 2B4 and NTB-A receptors bind the influenza viral hemagglutinin and co-stimulate NK cell cytotoxicity

Alexandra Duev-Cohen, Yotam Bar-On, Ariella Glasner, Orit Berhani, Yael Ophir, Francesca Levi-Schaffer, Michal Mandelboim, Ofer Mandelboim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Natural Killer (NK) cells are critical in the defense against viruses in general and against influenza in particular. We previously demonstrated that the activating NK cell receptor NKp46 is involved in the killing of influenza-virus infected cells through its interaction with viral hemagglutinin (HA). Furthermore, the recognition by NKp46 and consequent elimination of influenza infected cells were determined to be sialic-acid dependent. Here, we show that the human co-activating receptors 2B4 and NTB-A directly recognize the viral HA protein and co-stimulate killing by NK cells. We demonstrate that the 2B4/NTB-A-HA interactions require the sialylation of these receptors, and we identified the binding sites mediating these interactions. We also show that the virus counters these interactions through its neuraminidase (NA) protein. These results emphasize the critical role played by NK cells in eliminating influenza, a significant cause of worldwide morbidity and mortality.

Original languageAmerican English
Pages (from-to)13093-13105
Number of pages13
Issue number11
StatePublished - 15 Mar 2016

Bibliographical note

Funding Information:
This study was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement number 320473-BacNK. Further support came from the I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation and by the I-Core on Chromatin and RNA in Gene Regulation, the GIF foundation, the Lewis family foundation, the ICRF professorship grant, the Israeli Science Foundation, the Helmholtz Israel grant and the Rosetrees Trust (all to O.M.). O.M. is a Crown Professor of Molecular Immunology. FLS is supported by the ISF grant (472/15).


  • 2B4
  • Influenza
  • NK
  • NKp46
  • NTB-A


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