Phenotypic And Functional Characteristics Of A Novel Influenza Virus Hemagglutinin-Specific Memory Nk Cell

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 gamma interferon (IFN-gamma) response against influenza virus-infected cells, which could be reversed by pifithrin-mu, a p53-heat shock protein 70 (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.IMPORTANCE In this study, we demonstrate a novel hemagglutinin (HA)-specific NKp46(+) NKG2A(+) NK cell subset induced by influenza A virus infection. These memory NK cells show virus-specific decreased cytotoxicity and increased gamma interferon (IFN-gamma) on reencountering 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.