NK Cell Activation Pathways in Antiviral Immunity
NK cells express inhibitory and activating receptors that regulate their cytotoxicity. They are therefore able to induce the lysis of virus-infected cells that upregulate virus-derived proteins, as well as stress-inducible ligands, which are then recognized by NK-cell-activating receptors, such as NKp46 (Cerwenka and Lanier, 2001, Draghi et al., 2007, Duev-Cohen et al., 2016, Glasner et al., 2012). Future studies should investigate the expression of NK receptor ligands on SARS-CoV-2-infected cells in order to better understand the mechanisms underlying NK cell activation in COVID-19 disease. Further, secretion of IgG1 and IgG3 antibodies during SARS-CoV-2 infection (Amanat et al., 2020) may induce CD56dim CD16+ NK cell activation through Fc receptor recognition of antibodies either bound to surface antigens expressed on infected cells or to extracellular virions as immune complexes (Figure 2). This interaction might trigger both cytokine production by NK cells and lysis of infected cells through antibody-mediated cellular cytotoxicity (ADCC), as shown in influenza infection (Von Holle and Moody, 2019). Emerging data highlight the capacity for NK-mediated ADCC in response to naturally isolated SARS-CoV-1 anti-S IgG that crossreacts with SARS-CoV-2 S glycoprotein when transfected into Chinese hamster ovary (CHO) cells (Pinto et al., 2020). These findings suggest that triggering NK cell activation may not only contribute to the resolution of infection, but also contribute to the cytokine storm in ARDS.