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.
Introduction
Interferons (IFNs) are defined by their ability to induce resistance to viral infection. Three distinct types of IFNs are distinguished (type I, type II and type III), based on their structural features, receptor usage and biological activities. Although all types of IFNs stimulate innate and adaptive immune mechanisms that contribute to the clearance of viral infections, only type I and type III IFNs are directly produced in response to virus infections. Until recently, it was widely accepted that type I IFNs played an exclusive role as early mediators of the innate response to viruses, as well as regulators of the subsequent responses from elements of the adaptive immune system. Surprisingly, a group of proteins functionally similar to type I IFNs was discovered in 2002/2003 [1;2]. These proteins, now collectively known as type III IFNs and first designated as IFN-λs [1] or IL-28/29 [2], share with type I IFNs similar expression patterns and trigger common signal transduction cascades and sets of stimulated genes. Consequently, both types of I and type III IFNs share many biological activities, including the ability to induce an antiviral state in cells.
In humans, three functional IFN-λ genes are clustered on human chromosome 19 and encode highly homologous IFN-λ1, IFN-λ2 and IFN-λ3 proteins [1], whereas the type I IFN family includes 13 IFN-α proteins, and one of each IFN-β, IFN-ω, IFN-κ and IFN-ε, all encoded in a gene cluster on chromosome 9 [3]. Although the type I IFN genes lack introns, the coding regions of the IFN-λ genes are interrupted by 4 introns, and the positions of the introns with respect to the protein reading frames are conserved for the IFN-λ genes and for genes encoding IL-10-related cytokines [3;4]. The amino acid identity between type I and type III IFNs is very low, ranging from 15 to 20%. All IFN types belong to a family of α-helical-bundle cytokines that share common functional and structural characteristics and a common evolutionary origin [3;4]. In addition to type I and type III IFNs, in humans this cytokine family also contains one type II IFN (IFN-λ), and six IL-10-related cytokines (IL-10, IL-19, IL-20, IL-22, IL-24 and IL-26). In other species, the family can be further expanded with several viral orthologs, as well as type I IFNs that are not represented in the human genome. All these cytokines are collectively designated CRF2 cytokines because they interact with receptors from a specific receptor family known as the class II cytokine receptor family (CRF2) that is defined by common structural and functional features [5].
Although, type I and type III IFNs all possess intrinsic antiviral activities, they engage IFN type-specific receptor complexes for signaling. Type III IFNs signal through a heterodimeric IFN-λ receptor complex composed of a unique IFN-λR1 chain and the IL-10R2 chain that is also the second subunit of the receptor complexes for IL-10, IL-22 and IL-26 [3]. In contrast, all type I IFNs signal through a common cellular IFN-α/β receptor complex composed of two unique subunits, IFN-αR1 (IFNAR1) and IFN-αR2 (IFNAR2) [6].
Recent studies have started to uncover a unique role of IFN-λs in antiviral defense, and there is emerging evidence that IFN-λs may have functional importance beyond innate antiviral protection. Although the overall biological significance of IFN-λs remains to be determined, this report summarizes current information about the IFN-λ ligand-receptor system focusing on advances in our understanding of the biological activities of type III IFNs, the differences between the type I and type III IFNs, and the therapeutic potential of the IFN-λs.
Expression patterns
Co-expression of type I and type III IFNs in response to diverse viruses and various TLR agonists was reported in numerous in vitro and in vivo studies (reviewed in [7]), although differences in the expression of type I and type III IFNs have been documented. The similar expression patterns are due to the presence of common regulatory elements in the promoters of the type I and type III IFN genes (Fig. 1). Promoters of the IFN-λ genes contain predicted sites for binding of transcription factors AP1 (dimeric transcription factor containing members of the JUN, FOS, ATF and MAF protein families) and NF-κB (nuclear factor κB), and multiple virus response elements which are the sites for binding of various interferon regulatory factors (IRFs). All these factors are involved in the transcriptional regulation of the type I IFN genes [8]. The importance of the IRF and NF-κB pathways in the transcriptional regulation of the IFN-λ genes was also demonstrated [9;10]. It appears that the human IFN-λ1 and IFN-β genes have similar transcriptional regulation that is controlled by either IRF3 or IRF7, whereas IFN-λ2/3 genes, like most IFN-α genes, are more dependent on IRF7 [10]. This observation is important because IRF3 is constitutively and ubiquitously expressed in cells and, when activated upon viral entry, up-regulates expression of the IFN-β and IFN-λ1 genes. By contrast, IFN-α and IFN-λ2/3 genes are unresponsive to IRF3 alone and require IRF7 which is not constitutively expressed in most cell types but is induced in response to IFNs. In humans, both IFN-β and IFN-λ1 can prime cells for virus-induced IFN-α and IFN-λ2/3 production by up-regulating IRF7 expression. Thus, the expression pattern of the IFN-λ genes conforms to a similar positive feed-back mechanism that was first described for the type I IFN genes [11;12]. Similar to IFN-β, the IFN-λ1 gene represents an early response gene, whereas IFN-λ2/3 are likely to be expressed similar to IFN-αs, with delayed kinetics [13]. The regulation of type III IFNs may differ in mice, however, since there is no functional IFN-λ1 gene in the murine genome [14]. This multi-layered regulation allows the majority of nucleated cells to achieve finely tuned levels of IFN expression depending on the magnitude of viral infection. In contrast to most cell types, plasmacytoid dendritic cells (pDCs) constitutively express IRF7, enabling these cells to rapidly produce high levels of type I and type III IFNs upon stimulation [15;16]. Certain viruses or TLR agonists can induce IFN-λ production from several DC subsets, whereas other IFN-inducing stimuli act in a DC subset-restricted manner [16–19]. Thus, multiple cell types can co-produce type I and type III IFNs in response to viral infection.
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.
Despite these similarities in the pattern and regulatory mechanisms of type I and type III IFN expression, potential differences have emerged indicating that our understanding of IFN expression is incomplete. For example, it was reported that murine macrophages express high levels of type I IFN mRNAs after HSV infection, but do not up-regulate IFN-λ mRNA [20]. Human alveolar type II cells produced high levels of IFN-λs but not IFN-β in response to influenza A virus infection [21]. Importantly, recent studies revealed that IFN-λs appear to be the major IFN type produced by both murine and human airway epithelial cells in response to various respiratory viruses [22–24]. There is also evidence that NF-κB alone is able to induce IFN-λ expression after LPS treatment, independent of IRFs [25]. This may be attributed to a cluster of NF-κB binding sites in the distal promoter of the human IFN-λ1 gene (Fig. 1). In support of this observation, inhibition of the NF-κB pathway in murine DCs and in mice has a stronger effect on the expression levels of IFN-λs than on type I IFNs [26]. These studies suggest important differences in the transcriptional regulation of the type I and type III IFN genes: whereas type I IFN expression is strongly dependent on the cooperative action of multiple transcription factors, particularly IRFs and NF-κB, expression of type III IFNs can be induced through the independent action of IRFs or NF-κB. One important implication is that it may be more difficult for viruses to interfere with type III IFN production because both IRF and NF-κB signaling pathways would need to be simultaneously inhibited, whereas blocking IRFs is sufficient for the suppression of type I IFN production. However, at least one virus has evolved a mechanism to inhibit both type I and type III IFNs: the Yaba-like disease virus produces a soluble IFN antagonist able to bind and neutralize not only all type I IFNs but also type III IFNs, despite the considerable structural and sequence differences among these cytokines [6]. The ability of many viruses to successfully target pathways leading to IRF activation [27] may underlie the high levels of type III IFNs, but not type I IFNs, detected in the lungs of mice infected with influenza A virus [24], and elevated levels of type III IFNs but not type I IFNs in liver biopsies from patients with chronic hepatitis C virus infection [28]. Similarly, Hantaan virus triggered an early and high level of expression of IFN-λ1 mRNA, followed by IFN-λ2 mRNA, and a delayed and low level of IFN-β mRNA, with no significant change in levels of IFN-α message [13].
Receptor complex and signaling
As previously mentioned, the IFN-λs interact with a unique heterodimeric receptor consisting of IFN-λR1 (also known as IL-28RA, LICR or CRF2-12), and IL-10R2 (also known as IL-10Rβ), originally identified as the second subunit of the IL-10 receptor, and now known to be used in specific receptor complexes for other members of the IL-10 cytokine family [3;4]. The genes encoding receptors for IFNs and IL-10-related cytokines share a similar intron/exon structure, with the coding regions of the receptor genes divided into seven exons [4]. The IFN-λ gene and the IL-10R2 gene are positioned on human chromosome 1 and chromosome 21, respectively.
Crystal structures of human IFN-λ3 [29] and of human IFN-λ1 bound to the high affinity receptor subunit IFN-λR1 revealed a common topology with other CRF2 cytokines and a common mode of ligand-receptor interaction [30]. Similar to type I IFNs, IFN-λs are monomers in solution and interact with IFN-λR1 in a 1:1 ratio [1;29;30]. Thus, binding of a monomeric IFN-λ is likely to engage one molecule each of IFN-λR1 and IL-10R2 subunits (Fig. 2). Despite signaling through distinct receptor complexes, type I and type III IFNs trigger similar signaling pathways (Fig. 2), culminating in the activation of a transcriptional complex designated ISGF3 (IFN-stimulated gene factor 3) that is a unique and critical mediator of type I and type III IFN-induced biological activities. ISGF3 binds to the IFN-stimulated response element (ISRE) in the promoters of IFN-stimulated genes (ISGs) leading to gene transcription. Similar to the type I IFNs, IFN-λs also up-regulate expression of SOCS-3 providing the mechanism for negative regulation of IFN-λ signaling [31].
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.
IFNs can also induce signaling through pathways other than the canonical Jak-STAT pathway [32]. Similar to type I IFNs, IFN-λs trigger signaling through three major mitogen-activated protein kinase (MAPK) cascades: the extracellular signal-regulated kinase (ERK)-1/2; stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK); and p38 kinase [31;33]. IFN-λs also induce phosphorylation of Akt though the phosphatidylinositol 3-kinase (PI3K) pathway [31]. Engagement of Akt-mTOR and MEK/ERK pathways by IFN-λ results in the activation of the downstream kinases, p70 ribosomal protein S6 kinase (p70S6K) and p90 ribosomal protein S6 kinase 1 (RSK1), and their targets, the translational repressor 4E-BP1 and eukaryotic translation-initiation factor 4B (eIF4B), which regulate the initiation of mRNA translation [34]. However, the ability of IFN-λs to trigger these alternative pathways could be cell-type specific or altered in cancer cells, because phosphorylation of Akt, ERK and SAPK/JNK in response to IFN-λ was not detected in a panel of melanoma cell lines [35]. IFN-λ-induced phosphorylation of ERK was also not detected in Raji cells [33], whereas levels of phosphorylated p38 did not significantly changed in colorectal adenocarcinoma HT-29 cells [31].
It should be noted that the intensity of STAT activation and subsequent biological activities in response to IFN-λs, particularly inhibition of cell proliferation, is generally weaker than in response to type I IFNs [1;2;36]. This may result from the low level of IFN-λR1 expression in cells, or from differential ability to recruit and/or activate components of the intracellular signaling system. Overexpression of IFN-λR1 or a chimeric receptor that recapitulates IFN-λ signaling enables type III IFNs to induce strong signaling, leading to the pronounced anti-proliferative and pro-apoptotic responses in the transfected cells [37;38]. Interestingly, overexpression of IFN-λR1 in cells resulted in decreased antiviral activity of IFN-α [2], suggesting that IFNs may compete for common downstream signaling components. It is important to note that receptor complexes for type I and type III IFNs act independently of each other: in vitro and in vivo experiments demonstrated that either type I or type III IFN antiviral systems are functional in cells lacking receptors from the opposite receptor complex [20;33;39].
Except for the conserved STAT2 docking sites, the intracellular domains of IFN-λR1 and IFN-αR2c, the receptor chains respectively responsible for STAT activation within the type III and type I IFN receptor complexes, are very different, providing the basis for the possible engagement of distinct signaling pathways by the each type of IFNs. These elusive type I and type III IFN-specific pathways and subsequent biological activities are still to be identified by future experiments.
Functional significance of type III IFNs
Signaling though common pathways enables type I and type III IFNs to induce similar biological activities, particularly antiviral resistence, in responsive cells, presumably mediated by the induction of nearly identical sets of more than 300 ISGs [33;40;41]. Consequently, the most prominent biological function of type I and type III IFNs resides in their ability to induce an antiviral state in cells. However, important differences between the two antiviral systems first emerged from in vitro and ex vivo experiments, which revealed that not all cell types respond to type III IFNs: whereas different epithelial-like cell lines and primary keratinocytes are responsive to both types of IFNs, splenocytes, fibroblasts and endothelial cells do not seem to respond to IFN-λ [14]. Subsequent in vivo experiments elegantly demonstrated that the primary targets of type III IFNs are epithelial cells of the respiratory, gastro-intestinal and reproductive tracts [20;39;42–44]. The unique functional tissue-specificity of IFN-λs is due to the cell type-restricted pattern of IFN-λR1 expression; although all cells express receptors for type I IFNs, IFN-λR1 is primarily expressed in epithelial cells and specific subsets of immune cells [14;20;33;39;40;42–46]. In vivo studies further demonstrated that both type I and type III IFN systems are capable of providing efficient, comparable, and independent antiviral protection in epithelial tissues where receptors for both types of IFNs are expressed [20;39;43;44;47]. However, the IFN-λ antiviral system alone cannot provide full protection against systemic virus infections, presumably because these viruses infect cells that are not responsive to type III IFNs; for systemic infections, the functional type I IFN antiviral system is required. In contrast, antiviral protection of intestinal epithelial cells against GI viruses mainly relies on the action of the type III IFN antiviral system [48]. This recent study demonstrates that mice lacking a functional IFN-λ receptor complex had impaired control of oral rotavirus infection; the type I IFN system alone was unable to protect against rotaviruses, which infect intestinal epithelial cells. Importantly, systemic administration of IFN-λ, but not type I IFN, was able to induce an antiviral state in intestinal epithelial cells resulting in the suppression of rotavirus replication in the gut. Thus, the type III IFN system has a unique function in antiviral protection of intestinal epithelium that is independent of, and not overlapping with, the type I IFN antiviral system. Because expression of IFN-λs may be triggered by various bacteria-associated molecules, type III IFNs may be involved in the maintenance of GI tract homeostasis.
Concluding remarks
It is now clear that IFN-λs are important mediators of antiviral responses in mucosal/epithelial tissues, and are critically important for the protection of GI epithelium. Nevertheless, important aspects of IFN-λ biology require further experimental exploration to advance our understanding of the complex role of type III IFNs in overall immunity.
For example, although specific sets of immune cells such as pDCs [49] clearly respond to type III IFNs, it remains controversial whether IFN-λs affect any aspect of T cell biology, and whether effects of IFN-λs on T cells are direct or mediated by DCs. Thus, the current, immunomodulatory activities of IFN-λs are poorly defined and include apparently opposing functions such as: DC-mediated stimulation of either T-reg proliferation [50] or skewing toward Th1 differentiation [51]; DC-independent inhibition of Th2 cytokine production from CD4+ T cells [52]; induction of apoptosis of CD3+ T cells [53]; or augmentation of CTL effector functions during vaccination [54]. Clarification of these effects and expansion to understand IFN-λ effects on other immune cells, particularly those found in epithelial tissues, is a clear part of the research agenda.
The roles of IFN-λs in pathology or the potential of either these cytokines or anti-cytokine therapeutics are new areas for investigation. IFN-λs may also have a specialized role in the etiology of some diseases of epithelial tissue, and in the treatment of viral infections of these and other responsive tissues. The tissue-restricted expression of the IFN-λ receptor has several implications, including the likelihood that IFN-λ therapy may cause fewer and/or milder side effects than IFN-α therapy which is accompanied by numerous side effects. In the airway and lung, for example, there is strong evidence that the type III IFN system play an important role in the pathology of asthma [51;55]. Also, because IFN-λs are active on lung epithelial cells and are important mediators in innate responses to respiratory viral infections [1;55], it is possible that intranasal delivery of IFN-λs could be effective treatment and/or preventive measure against numerous respiratory viruses, particularly against viruses which are poor IFN-inducers. Moreover, IFN-λ therapy may represent a novel approach to prevention and/or treatment of respiratory virus-triggered asthma exacerbations [51;55].
Pegylated IFN-λ1 is undergoing clinical trials for the treatment of chronic hepatitis C infection [56]. Human primary and cultured hepatocytes respond to type III IFNs, and IFN-λs exhibit antiviral activities against HCV and HBV in these cells [40;41;57;58]. Moreover, the importance of IFN-λs for antiviral immunity against HCV in humans is highlighted by recent reports about several single nucleotide polymorphisms (SNPs) near the IFN-λ3 gene, which seem to affect IFN-λ expression levels [59–61], were correlated with the spontaneous clearance of HCV [62], and were also associated with sustained virologic response (SVR) in patients with chronic HCV undergoing pegylated IFN-α/ribavirin (pegIFN-α/RBV) combination therapy [60,61,63]. On the other hand, the IFN-λ antiviral system appears to play minimal if any role in the protection of mice against hepatotropic viruses [39], so the results of the human clinical trials are of great interest.
The potential broad roles of IFN-λs in immune function also opens questions in autoimmunity and cancer therapy. By analogy with type I IFNs, it remains to be seen whether IFN-λs are involved in the development or can be used for the treatment of other inflammatory or autoimmune diseases such as systemic lupus erythematosus (SLE) [64], inflammatory bowl disease (IBD) [53], multiple sclerosis (MS) [65] or rheumatoid arthritis (RA). Furthermore, the finding that IFN-λs display potent antitumor activities in murine models of cancer [14;66–68], motivates an exploration of their potential as anti-cancer therapeutics. Thus, although the overall importance of the IFN-λs in host immune responses remains to be fully determined, accumulating evidence suggests that IFN-λs occupy a unique functional niche in the regulation of well-balanced immunity and may have strong and diverse therapeutic potential.
Highlights
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The interferon (IFN) family was recently expanded with the discovery of type III IFNs
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Type III IFNs or IFN-λs, also known as IL-28/29, are directly induced by viral infection
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IFN-λs, together with type I IFNs, function as early mediators of the innate antiviral response
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IFN-λs engage a specific receptor complex to induce antiviral state in cells
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IFN-λs possess unique biological activities in and beyond innate antiviral immunity
Acknowledgments
I thank Dr. Jerome Langer for the critical reading of the review and helpful suggestions. This study was supported in part by the US Public Health Services Grants RO1 AI057468, R21 AI076937 and U01 AI082994 from the NIAID, and TIL Award from Alliance for Lupus Research.
Footnotes
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