Type III interferon (IFN-λ) induces signaling cascades and antiviral functions that are very similar to those induced by type I interferon, but signal through a unique IFN-λR1–IL-10Rβ heterodimeric receptor. In Immunity, Galani et al. show that IFN-λ is the first interferon produced during influenza virus infection in mice and mediates an antiviral response without inducing inflammation. IFN-λ is induced at day 1 post-infection, before, and independently of, type I interferon, and is produced mostly by the respiratory epithelium. Ifnlr1−/− mice have increased viral load, neutrophil infiltration, IFN-α production and aggravated pathology in the lung early during infection compared with wild-type or Ifnar1−/− mice. Neutrophils and epithelial cells are the main subsets of cells that express IFN-λR1 and respond to IFN-λ. In neutrophils, both IFN-λ and type I interferon trigger the expression of interferon-stimulated genes and pattern-recognition receptors, whereas only type I interferon triggers the production of proinflammatory cytokines and chemokines. IFN-λ treatment early after infection inhibits viral spread and reduces inflammation.

Immunity 46, 875–890 (2017)