IFNλs are dual function cytokines mediating antiviral activity and damage control.
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IFNλs confer initial antimicrobial protection at anatomical barriers without provoking unnecessary inflammation.
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IFNλs exhibit immune regulatory and host protective actions reminiscent of IL-10.
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IFNλs form novel therapeutics with the beneficial actions of type I IFNs but lacking their pro-inflammatory side effects.
Lambda interferons (IFNλs, type III IFNs or interleukins-28/29) were described fifteen years ago as novel cytokines sharing structural and functional homology with IL-10 and type I IFNs, respectively. IFNλs engage a unique receptor complex comprising IFNLR1 and IL10R2, nevertheless they share signaling cascade and many functions with type I IFNs, questioning their possible non-redundant roles and overall biological importance. Here, we review the latest evidence establishing the primacy of IFNλs in front line protection at anatomical barriers, mediating antiviral immunity before type I IFNs. We also discuss their emerging role in regulating inflammation and limiting host damage, a major difference to type I IFNs. IFNλs come thus to light as dual function cytokines mediating antiviral immunity and damage control.