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

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

doi:10.18632/oncotarget.7597

Alexandra Duev-Cohen, Ofer Mandelboim + Show 6 more

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https://doi.org/10.18632/oncotarget.7597

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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.

Highlights

Natural Killer (NK) cells are bone marrow derived lymphocytes that are part of the innate immune system [1]
We previously showed that NKp44 and NKp46 bind to HA and this leads to NK-mediated killing of influenza virus infected cells [11]
To test NK cell-mediated killing of cells coated with influenza, bulk primary human NK cell cultures were incubated with antiNKp46 polyclonal antibodies and assayed against JEG3 cells in the presence or absence of A/Puerto Rico/8/34 H1N1(PR8) (Figure 1A) or A/Brisbane/59/2007 H1N1

Summary

Introduction

NK cells are bone marrow derived lymphocytes that are part of the innate immune system [1] They are able to kill virus-infected cells, bacteria, parasites and tumor cells [2]. Killing by NK cells is mediated by a balance between inhibitory and activating signals derived from inhibitory and activating receptors. The inhibitory signals are primarily delivered upon binding of the NK inhibitory receptors to MHC class I proteins [4]. The NKp30 receptor recognizes tumor ligands such as B7H6 [6], and viral ligands such as pp65 [7] and the viral HA proteins of poxvirus and vaccinia virus [8]. The NKp44 receptor binds to viral HA [14] and to tumor ligands, such as PCNA [15] and MLL5 [16]

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