<scp>NK</scp> cells exacerbate the pathology of influenza virus infection in mice

<jats:p><jats:styled-content style="fixed-case">NK</jats:styled-content> cells offer a first line of defense against viruses and are considered beneficial to the host during infection. Nevertheless, little is understood regarding the phenotype and function of <jats:styled-content style="fixed-case">NK</jats:styled-content> cells in the lung during influenza virus infection. We found that the frequency of <jats:styled-content style="fixed-case">NK</jats:styled-content> cells in mouse lung increased during influenza infection, with the majority of a mature phenotype. Cell surface <jats:styled-content style="fixed-case">CD</jats:styled-content>107a and intracellular <jats:styled-content style="fixed-case">IFN</jats:styled-content>‐γ were detected in cells expressing multiple <jats:styled-content style="fixed-case">NK</jats:styled-content>‐cell receptors in infected lung, suggesting that <jats:styled-content style="fixed-case">NK</jats:styled-content> cells were activated during infection. The activating receptor <jats:styled-content style="fixed-case">NK</jats:styled-content>p46 was predominantly negative on such cells, possibly as a result of encountering influenza <jats:styled-content style="fixed-case">HA</jats:styled-content>. Depletion of <jats:styled-content style="fixed-case">NK</jats:styled-content> cells in vivo with anti‐asialo <jats:styled-content style="fixed-case">GM</jats:styled-content>1 or anti‐<jats:styled-content style="fixed-case">NK</jats:styled-content>1.1 reduced mortality from influenza infection and surviving mice recovered their body weight. Pathology induced by <jats:styled-content style="fixed-case">NK</jats:styled-content> cells was only observed with high, not medium or low‐dose influenza infection, indicating that the severity of infection influences <jats:styled-content style="fixed-case">NK</jats:styled-content>‐cell‐mediated pathology. Furthermore, adoptive transfer of <jats:styled-content style="fixed-case">NK</jats:styled-content> cells from influenza‐infected lung, but not uninfected lung, resulted in more rapid weight loss and increased mortality of influenza‐infected mice. Our results indicate that during severe influenza infection of the lung, <jats:styled-content style="fixed-case">NK</jats:styled-content> cells have a deleterious impact on the host, promoting mortality.</jats:p>