Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control

Abstract

Lambda interferons (IFNls, 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. IFNls 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 IFNls 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. IFNls come thus to light as dual function cytokines mediating antiviral immunity and damage control.

Type III interferons: Balancing tissue tolerance and resistance to pathogen invasion

“…In fact, both cytokine receptor complexes activate the same JAK family kinases, except for JAK2, which is activated only downstream of IFN-λ (Odendall et al, 2014;Odendall and Kagan, 2015). Activated JAKs in turn recruit and phosphorylate STAT family members, which then migrate into the nucleus and, together with IFN-regulatory factor 9 (IRF9), mediate the transcription of overlapping sets of IFN-stimulated genes (ISGs; Kotenko, 2011;Lazear et al, 2015aLazear et al, , 2019Andreakos et al, 2019;Pervolaraki et al, 2019). Finally, both classes of cytokines are induced in response to viral infection and contribute to antiviral immunity (Odendall and Kagan, 2015;Kotenko, 2011;Lazear et al, 2019).…”

Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

“…The airway epithelial cell (AEC) is the point of entry of respiratory viruses and orchestrates the airway immune response in humans 1–5 . Although airway antiviral responses involve many cells, resulting in a complex cytokine milieu, there is agreement that interferon (IFN)‐lambda (type III‐IFN‐λ1) is an antiviral molecule primarily produced by epithelial cells 6–15 . The IFN‐lambda receptor is also predominately expressed in epithelial cells, suggesting that the IFN‐lambda system has evolved to specifically protect mucosal surfaces via paracrine and autocrine mechanisms 6–15 .…”

“…Although airway antiviral responses involve many cells, resulting in a complex cytokine milieu, there is agreement that interferon (IFN)‐lambda (type III‐IFN‐λ1) is an antiviral molecule primarily produced by epithelial cells 6–15 . The IFN‐lambda receptor is also predominately expressed in epithelial cells, suggesting that the IFN‐lambda system has evolved to specifically protect mucosal surfaces via paracrine and autocrine mechanisms 6–15 . Notably, there is experimental evidence that IFN lambda provides critical defence against respiratory viruses, including influenza virus and respiratory syncytial virus (RSV) 6–15 .…”

“…The IFN‐lambda receptor is also predominately expressed in epithelial cells, suggesting that the IFN‐lambda system has evolved to specifically protect mucosal surfaces via paracrine and autocrine mechanisms 6–15 . Notably, there is experimental evidence that IFN lambda provides critical defence against respiratory viruses, including influenza virus and respiratory syncytial virus (RSV) 6–15 . Emergent data indicate that it may also play an important role against SARS‐CoV‐2 and other type of coronavirus infections 16–21 …”

Structure-based glycoengineering of interferon lambda 4 enhances its productivity and anti-viral potency

“…All three IFN members activate the JAK/STAT pathway and induce interferonstimulated gene (ISG) expression by binding to their respective receptors: IFNαR1 and IFNαR2 for type I interferon (IFNα/β), IFNγR1 and IFNγR2 for type II interferon (IFNγ), and IFNλR1 and IL10Rβ for type III interferon (IFNλ1~4) [1,4]. In contrast to types I and II, type III IFN was only recently identified and plays not only antiviral functions but also novel immunomodulatory functions in oncology and autoimmune diseases [5,6]. IFNλ1~3 were identified through computational based prediction from genome sequencing [7,8] and IFNλ4 was discovered in genome-wide association studies (GWAS) on hepatitis C virus (HCV)-infected patients [9].…”