Influenza infection enhances antibody-mediated NK cell functions via Type I interferon dependent pathways.

NK cells are an important component in the control of influenza infection, acting to both clear virus-infected cells and release antiviral cytokines. Engagement of CD16 on NK cells by antibody-coated influenza-infected cells results in antibody-dependent cellular cytotoxicity (ADCC). Increasing the potency of antibody-mediated NK cell activity could ultimately lead to improved control of influenza infection. To understand if NK cells can be functionally enhanced following exposure to influenza virus-infected cells, we co-cultured human PBMCs with influenza-infected human alveolar epithelial (A549) cells and evaluated the capacity of NK cells to mediate antibody-dependent functions. Pre-incubation of PBMCs with influenza-infected cells markedly enhanced the ability of NK cells to respond to immune complexes containing HA and anti-HA antibodies or transformed allogenic cells in the presence or absence of a therapeutic monoclonal antibody. Cytokine multiplex, RNA sequencing, supernatant transfer, trans-well and cytokine blocking/supplementation experiments showed that type I interferons released from PBMCs were primarily responsible for the influenza-induced enhancement of antibody-mediated NK cell functions. Importantly, the influenza-mediated increase in antibody-dependent NK cell functionality was mimicked by the type I interferon agonist poly(I:C). We conclude that type I interferon secretion induced by influenza virus infection enhances the capacity of NK cells to mediate ADCC, and this pathway could be manipulated to alter the potency of anti-influenza therapies and vaccines. Significance: Protection from severe influenza may be assisted by antibodies that engage NK cells to kill infected cells through ADCC. Studies have primarily focused on antibodies that have ADCC activity, rather than the capacity of NK cells to become activated and mediate ADCC during an influenza infection. We found that type I interferon released in response to influenza infection primes NK cells to become highly reactive to anti-influenza ADCC antibodies. Enhancing the capacity of NK cells to mediate ADCC could assist in controlling influenza virus infections.