Zheng J, Wen L, Yen HL, Liu M, Liu Y, Teng O, Wu W. Phenotypic and functional characteristics of a novel influenza hemagglutinin-specific memory NK cell. J Virol. 2021 Apr 7:JVI.00165-21
Immune memory represents the most efficient defense against invasion and transmission of infectious pathogens. In contrast to memory T and B cells, the roles of innate immunity in recall responses remain inconclusive. In this study, we identified a novel mouse spleen NK cell subset expressing NKp46 and NKG2A induced by intranasal influenza virus infection. These memory NK cells specifically recognize N-linked glycosylation sites on influenza hemagglutinin (HA) protein. Different from memory-like NK cells reported previously, these NKp46+NKG2A+ memory NK cells exhibited HA-specific silence of cytotoxicity but increase of IFN-γ response against influenza virus-infected cells, which could be reversed by Pifithrin-μ, a p53-HSP70 signaling inhibitor. During recall responses, splenic NKp46+NKG2A+ NK cells were recruited to infected lung and modulated viral clearance of virus and CD8+ T cell distribution, resulting in improved clinical outcomes. This long-lived NK memory bridges innate and adaptive immune memory response and promotes the homeostasis of local environment during recall response.ImportanceIn this study, we demonstrate a novel HA-specific NKp46+NKG2A+ NK cell subset induced by influenza A virus infection. These memory NK cells show virus-specific decreased cytotoxicity and increased IFN-γ on re-encountering the same influenza virus antigen. In addition, they modulate host recall responses and CD8 T cell distribution, thus bridging the innate immune and adaptive immune responses during influenza virus infection.
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