Phenotypic and Functional Characteristics of a Novel Influenza Virus Hemagglutinin-Specific Memory NK Cell

J Virol. 2021 May 24;95(12):e00165-21. doi: 10.1128/JVI.00165-21. Print 2021 May 24.


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-γ) response against influenza virus-infected cells, which could be reversed by pifithrin-μ, 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-γ) 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.

Keywords: NK; cytotoxicity; gamma IFN; glycosylation; hemagglutinin; immune memory; influenza virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Ly / analysis
  • Antigens, Ly / metabolism
  • Benzothiazoles / pharmacology
  • CD8-Positive T-Lymphocytes / immunology
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Dendritic Cells / immunology
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Immunologic Memory*
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza A Virus, H9N2 Subtype / immunology
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily C / analysis
  • Natural Cytotoxicity Triggering Receptor 1 / analysis
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism
  • Orthomyxoviridae Infections / immunology*
  • Spleen / cytology
  • Spleen / immunology
  • Toluene / analogs & derivatives
  • Toluene / pharmacology


  • Antigens, Ly
  • Benzothiazoles
  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Klrc1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily C
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Toluene
  • Interferon-gamma
  • pifithrin