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

// Alexandra Duev-Cohen 1 , Yotam Bar-On 1 , Ariella Glasner 1 , Orit Berhani 1 , Yael Ophir 1 , Francesca Levi-Schaffer 2 , Michal Mandelboim 3 and Ofer Mandelboim 1 1 The Lautenberg Center of General and Tumor Immunology, The Hebrew University Hadassah Medical School, IMRIC, Jerusalem, Israel 2 Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel 3 Central Virology Laboratory, Ministry of Health, Public Health Services, Chaim Sheba Medical Center, Ramat-Gan, Israel Correspondence to: Ofer Mandelboim, email: // Keywords : influenza, NK, 2B4, NTB-A, NKp46 Received : October 18, 2015 Accepted : January 13, 2016 Published : February 22, 2016 Abstract 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.