IFN-λs

Abstract

For decades, type I IFNs have been considered indispensable and unique antiviral mediators for the activation of rapid innate antiviral protection. However, the recent discovery of type III IFNs is challenging this paradigm. Since their identification in 2002/2003 by two independent groups, type III IFNs or IFN-λs, also known as IL-28/29, have been the subject of increased study with consequent recognition of their importance in virology and immunology. Initial reports suggested that IFN-λs functionally resemble type I IFNs. Although IFN-λs and classical type I IFNs (IFN-α/β) utilize distinct receptor complexes for signaling, both types of IFNs activate similar intracellular signaling pathways and biological activities, including the ability to induce antiviral state in cells, and both type I and type III IFNs are induced by viral infection. However, different antiviral potency, pattern of their induction and differential tissue expression of their corresponding receptor subunits suggest that the type I and type III IFN antiviral systems do not merely duplicate each other. Recent studies have started to reveal unique biological activities of IFN-λs in and beyond innate antiviral immunity.

Fig. 1. Model of the IFN expression

A variety of sensors are employed by cells to recognize molecules associated with pathogens or the damage to the host cells caused by pathogens. When engaged, these sensors trigger several overlapping pathways leading to the activation of transcriptional factors that induce expression of the type I and type III IFN genes [69]. Two classes of transcription factors, nuclear factor κB (NF-κB) and interferon regulatory factors (IRFs), are crucially important for the induction of type I and type III IFN expression. AP1 transcription factor (dimeric transcription factor containing members of the JUN, FOS, ATF and MAF protein families) is involved in the regulation of transcription of the IFN-β gene [8]. AP1 binding sites are also predicted in the promoters of the IFN-λs genes, but their functions have not been studied.

Fig. 2. Model of the IFN-λ receptor system, in relation to the type I IFN receptor system

Type I and type III IFNs signal through unique receptor heterodimers. The functional IFN-λ receptor complex is composed of IFN-λR1 and IL-10R2 chains. IFN-λ-induced receptor engagement leads, via the activation of receptor-associated Jak kinases, Jak1 and Tyk2, to the tyrosine phosphorylation of the IFN-λR1 intracellular domain and subsequent activation of latent transcription factors of the STAT family: STAT1, STAT2, STAT3, STAT4, and STAT5 [1;37]. Phosphorylated STATs form various homo- and heterodimers, translocate to the nucleus, and bind to specific DNA elements in the promoters of IFN-stimulated genes (ISGs) leading to gene transcription and induction of IFN-λ-specific biological activities, such as upregulation of MHC class I antigen expression, activation of antiviral protection, anti-proliferative response and antitumor activities. STAT1-STAT2 heterodimers interact with a DNA-binding protein IRF9 to form IFN-stimulated gene factor 3 (ISGF3) complex that binds the IFN-stimulated response element (ISRE). Activated STAT1 can also homodimerize and bind to the GAS (gamma-activated sequence) element. Latent STAT2 is recruited to the IFN-λ receptor complexes through the interaction of STAT2 SH2 domain with two specific phosphotyrosine based motifs (Tyr343 or Tyr517) within the intracellular domain of IFN-λR1 that are similar to motifs found in the IFN-α receptors [37]. Activation of STAT2 requires the presence of either Tyr343 or Tyr517 of IFN-λR1, whereas STAT4 phosphorylation, and to some extent STAT1 and STAT3 phosphorylation, can proceed independently of IFN-λR1 tyrosine residues. The ability of IFN-λs to induce antiviral and antiproliferative activities is completely dependent on Tyr343 or Tyr517 of IFN-λR1, demonstrating that the activation of STAT2 is pivotal for these biological activities [37]. Not shown here, but mentioned in the text, are alternate signaling pathways, in addition to the Jak-Stat pathways illustrated here.