Research ArticleFUNGAL INFECTION

Type III interferon is a critical regulator of innate antifungal immunity

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Science Immunology  06 Oct 2017:
Vol. 2, Issue 16, eaan5357
DOI: 10.1126/sciimmunol.aan5357

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Type III interferons prime neutrophils

Type I interferons (IFNs) have a well-established role in antiviral immunity. Here, Espinosa et al. demonstrate that type III IFNs (IFN-λs) play an essential role in driving antifungal responses. By studying immune responses to Aspergillus fumigatus (Af) in mice lacking receptors for type I or type III IFNs, the authors found monocyte-derived type I IFNs to be key drivers of IFN-λ production. Although they could not pin down the sources of IFN-λ, they have identified neutrophils as the functional target of IFN-λs. Selective deletion of IFN-λ receptor in neutrophils caused mice to succumb to Af infection. By studying immune responses to Af, the authors have uncovered the importance of type III IFNs in antifungal immunity.

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.

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