Type III interferon is a critical regulator of innate antifungal immunity

Sci Immunol. 2017 Oct 6;2(16):eaan5357. doi: 10.1126/sciimmunol.aan5357.

Abstract

Type III interferons (IFN-λs) are the most recently found members of the IFN cytokine family and engage IFNLR1 and IL10R2 receptor subunits to activate innate responses against viruses. We have identified IFN-λs as critical instructors of antifungal neutrophil responses. Using Aspergillus fumigatus (Af) as a model to study antifungal immune responses, we found that depletion of CCR2+ monocytes compromised the ability of neutrophils to control invasive fungal growth. Using an unbiased approach, we identified type I and III IFNs as critical regulators of the interplay between monocytes and neutrophils responding to Af We found that CCR2+ monocytes are an important early source of type I IFNs that prime optimal expression of IFN-λ. Type III IFNs act directly on neutrophils to activate their antifungal response, and mice with neutrophil-specific deletion of IFNLR1 succumb to invasive aspergillosis. Dysfunctional neutrophil responses in CCR2-depleted mice were rescued by adoptive transfer of pulmonary CCR2+ monocytes or by exogenous administration of IFN-α and IFN-λ. Thus, CCR2+ monocytes promote optimal activation of antifungal neutrophils by initiating a coordinated IFN response. We have identified type III IFNs as critical regulators of neutrophil activation and type I IFNs as early stimulators of IFN-λ expression.

Publication types

  • Comment

MeSH terms

  • Adaptive Immunity
  • Animals
  • Aspergillus fumigatus / growth & development
  • Aspergillus fumigatus / immunology
  • Aspergillus fumigatus / pathogenicity
  • Cell Line
  • Humans
  • Immunity, Innate*
  • Interferon Lambda
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Interferon-alpha / administration & dosage
  • Interferon-alpha / immunology
  • Interferons / administration & dosage
  • Interferons / genetics
  • Interferons / immunology*
  • Interferons / metabolism
  • Invasive Fungal Infections / immunology*
  • Invasive Fungal Infections / microbiology
  • Mice
  • Monocytes / immunology
  • Neutrophils / immunology
  • Receptors, CCR2 / deficiency
  • Receptors, CCR2 / immunology
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, Interferon / deficiency
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology

Substances

  • Ccr2 protein, mouse
  • IFNLR1 protein, human
  • IFNLR1 protein, mouse
  • Interferon Type I
  • Interferon-alpha
  • Receptors, CCR2
  • Receptors, Cytokine
  • Receptors, Interferon
  • Interferons
  • Interferon Lambda