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The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in

Madlen Loebel1, Luise Holzhauser2, Jelka A Hartwig1

  • 1Institute of Medical Immunology, Charité, Augustenburger Platz 1, 13353 Berlin, Germany.

European Heart Journal
|November 15, 2017
PubMed
Abstract

Insights

Forkhead box protein 3 (Foxo3) regulates natural killer (NK) cell responses. Foxo3 deficiency enhances NK cell activity, improving viral myocarditis control, but a common human polymorphism may impair antiviral immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Forkhead box protein 3 (Foxo3) is a transcription factor with known roles in cell metabolism, survival, and inflammatory diseases.
  • Mechanistic insights into Foxo3's specific effects on immune responses, particularly in viral infections, remain limited.

Purpose of the Study:

  • To investigate the role of Foxo3 in regulating natural killer (NK) cell responses.
  • To determine the impact of Foxo3 on the course of viral myocarditis.

Main Methods:

  • A mouse model of coxsackievirus B3-induced myocarditis was used, comparing wild-type (WT) and Foxo3-deficient (Foxo3-/-) mice.
  • Analysis included viral load, immune cell infiltration, cytokine levels, NK cell activation markers (CD69, NKp46), cytotoxicity, and microRNA-155 expression.
  • Human NK cells and patients with a specific FOXO3 single nucleotide polymorphism (SNP) were also studied.

Main Results:

  • Foxo3-/- mice exhibited reduced viral titers and pro-inflammatory cytokines, alongside enhanced NK cell activity (increased CD69, NKp46, effector cell frequencies, and cytotoxicity) at early stages of viral myocarditis.
  • Elevated microRNA-155 in Foxo3-/- NK cells correlated with increased interferon-gamma (IFNγ) production.
  • Healthy humans with the longevity-associated FOXO3 SNP rs12212067 showed reduced NK cell IFNγ production and cytotoxicity, and viral cardiomyopathy patients with this SNP had poorer outcomes.

Conclusions:

  • Foxo3 plays a significant role in modulating NK cell function and antiviral innate immunity.
  • While enhanced FOXO3 activity might be beneficial in chronic inflammatory conditions, it appears detrimental for controlling acute viral infections.

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