JOURNAL OF INTERFERON & CYTOKINE RESEARCH OVERVIEW Volume 30, Number 8, 2010 ª Mary Ann Liebert, Inc. DOI: 10.1089/jir.2010.0078 Interferon-Lambda: A New Addition to an Old Family Raymond P. Donnelly1 and Sergei V. Kotenko2 The discovery and initial description of the interferon-l (IFN-l) family in early 2003 opened an exciting new chapter in the field of IFN research. There are 3 IFN-l genes that encode 3 distinct but highly related proteins denoted IFN-l1, -l2, and -l3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Collectively, these 3 cytokines comprise the type III subset of IFNs. They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through a heterodimeric receptor complex that is different from the receptors used by type I or type II IFNs. Although type I IFNs (IFN-a/b) and type III IFNs (IFN-l) signal via distinct receptor complexes, they activate the same intracellular signaling pathway and many of the same biological activities, including antiviral activity, in a wide variety of target cells. Consistent with their antiviral activity, expression of the IFN-l genes and their corresponding proteins is inducible by infection with many types of viruses. Therefore, expression of the type III IFNs (IFN-ls) and their primary biological activity are very similar to the type I IFNs. However, unlike IFN-a receptors which are broadly expressed on most cell types, including leukocytes, IFN-l receptors are largely restricted to cells of epithelial origin. The potential clinical importance of IFN-l as a novel antiviral therapeutic agent is already apparent. In addition, preclinical studies by several groups indicate that IFN-l may also be useful as a potential therapeutic agent for other clinical indications, including certain types of cancer. Introduction now recognized (type I, II, and III) based on their structural features, receptor usage and biological activities. Although n early 2003, 2 groups independently reported the dis- all IFNs are important mediators of antiviral protection, Icovery of a trio of novel interferon (IFN)-like cytokines that their roles in antiviral defense vary. Type I IFNs (IFN-a/b/ are referred to as either IFN-l1, -l2, and -l3orinterleukin-29 o/e/k in humans) possess strong intrinsic antiviral activity, (IL-29), IL-28A, and IL-28B, respectively (Kotenko and others and are able to induce a potent antiviral state in a wide 2003; Sheppard and others 2003). Both groups also identified variety of cells (Levy and Garcia-Sastre 2001; Samuel 2001). and characterized the novel receptor, IFN-lR1 (also known as TheessentialroleofthetypeIIFNsintheinductionof IL-28RA), through which these cytokines mediate their antiviral resistance has been clearly demonstrated using biological activities. Since their original description in 2003, type I IFN receptor knockout mice because such animals are much has been learned about this exciting new group of cy- highly susceptible to many viral infections (Mu¨ ller and tokines and their functions. In the fall of 2009, several of the others 1994; Hwang and others 1995; Steinhoff and others leading scientists who are conducting IFN-l-related research 1995). In contrast, studies with IFN-g and IFN-g receptor presented summaries of their studies in a special focus session knock-out mice (Dalton and others 1993; Huang and others on these cytokines during the annual meeting of the Interna- 1993; Lu and others 1998) as well as analysis of humans tional Society for Interferon and Cytokine Research in Lisbon, who possess inherited genetic mutations of the IFN-g re- Portugal. This special issue of Journal of Interferon & Cytokine ceptor (Dorman and others 2004; Novelli and Casanova Research includes a series of review articles by all of the 2004) revealed that antiviral activity is not the primary speakers who presented in that special session as well as biological function of IFN-g. several additional invited experts. This collection of articles IFN-g is classified as a Th1-type cytokine that stimulates provides an excellent summary of the current state of cell-mediated immune responses that are critical for the de- knowledge regarding many aspects of IFN-l biology. velopment of host protection against pathogenic intracellular IFNs are key cytokines in the establishment of a multi- microorganisms such as Mycobacterium tuberculosis (Bach and faceted antiviral response. Three distinct types of IFNs are others 1997; Boehm and others 1997; Pestka and others 1997). 1Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland. 2Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey. 555 556 DONNELLY AND KOTENKO IFN-g also plays a central role in the development of anti- IFNs exhibit about *5%–18% identity with either type I tumor immune responses, and it can amplify the induction of IFNs or the IL-10-related cytokines. antiviral activity by IFN-a or -b. Therefore, type I and type II The IFN-l proteins bind and signal through a receptor IFNs often work together to activate a variety of innate and complex composed of the unique IFN-lR1 chain (also adaptive immune responses that result in the induction of known as IL-28RA) and the shared IL-10R2 chain which is effective antitumor immunity and the elimination of viral also a part of the receptor complexes for IL-10, IL-22, and infections (Biron 2001; Le Bon and Tough 2002; Pestka and IL-26 (Kotenko and others 1997, 2001; Xie and others 2000; others 2004b). Donnelly and others 2004; Ho¨randothers2004;Sheikhand IFNs are part of the larger family of class II cytokines that others 2004). In contrast, all type I IFNs exert their biolog- also includes 6 IL-10-related cytokines: IL-10, IL-19, IL-20, ical activities through a heterodimeric receptor complex IL-22, IL-24, and IL-26 (Kotenko 2002; Renauld 2003; Pestka composed of the IFN-aR1 (IFNAR1) and IFN-aR2 (IFNAR2) and others 2004a) as well as several viral IL-10-related chains, and type II IFN (IFN-g) engages the IFN-gR1 cytokines (Kotenko and Langer 2004). IFNs and the IL-10- (IFNGR1) and IFN-gR2 (IFNGR2) chains to assemble its related cytokines can be grouped into the same family functional receptor complex. Although the IFN-lsdonot because they all signal via receptors that share common use the IFN-a receptor complex for signaling, signaling motifs in their extracellular domains. These receptors through either IFN-l or IFN-a receptor complexes results in comprise the class II cytokine receptor family (CRF2). the activation of the same Jak-STAT signal transduction Consequently, IFNs and the IL-10-related cytokines are cascade. sometimes referred to as ‘‘CRF2 cytokines.’’ The type I IFN IFN-l binds initially to the IFN-lR1 chain, and the binary family in humans consists of 13 IFN-a species and a single complex formed by the association of IFN-l with the IFN- species of IFN-b,IFN-k,IFN-o,andIFN-e (LaFleur and lR1 chain causes a rapid conformational change that facili- others 2001; Hardy and others 2004; Langer and others tates recruitment of the second receptor chain, IL-10R2, to the 2004; Pestka and others 2004b). There is only one type II complex. Once assembly of the ternary complex is complete, IFN known as IFN-g.Althoughthetertiarystructureof the receptor-associated Janus tyrosine kinases, Jak1 and IFN-g resembles that of IL-10, its primary structure has Tyk2, mediate trans-phosphorylation of the receptor chains diverged the most from all of the CRF2 ligands. The most which results in the formation of phosphotyrosine-containing recent addition to the CRF2 family, the type III IFNs or peptide motifs on the intracellular domain (ICD) of the IFN- IFN-ls, demonstrate structural features of the IL-10-related lR1 chain that provide transient docking sites for latent cytokines but also induce antiviral activity in a variety of preformed cytosolic STAT proteins, including STAT1 and target cells, which supports their functional classification as STAT2. Signaling through type I (IFN-a/b) or type III (IFN-l) a new type of IFNs (Kotenko and others 2003; Sheppard IFN receptor complexes results in the formation of a tran- and others 2003). In humans, 3 distinct but closely related scription factor complex known as IFN-stimulated gene IFN-l proteins, IFN-l1, -l2, and -l3 (also known as IL-29, factor 3 (ISGF3). This complex consists of 3 proteins, STAT1, IL-28A, and IL-28B, respectively) form the type III IFN STAT2, and IFN regulatory factor-9 (IRF-9) (also known as family. Phylogenetically, the IFN-l genes reside somewhere ISGF3g or p48). Once assembled, ISGF3 then translocates between the type I IFN and IL-10 gene families (Fig. 1). to the nucleus where it binds to IFN-stimulated response Amino acid sequence comparisons show that the type III elements in the promoters of various ISGs. Consequently, the A B IFN-l2 IFN-l2 IFN-l3 IFN-l3 IFN-l1 IFN-l1 IL-19 IFN-e IL-20 IFN-k IL-10 IFN-a IL-26 IFN-w IL-22 IFN-b IL-24 FIG. 1. A phylogenetic alignment of the class II cytokine family genes. Alignment of the human interferon-l (IFN-l) genes with either (A) the human type I IFN genes or (B) the human interleukin-10 (IL-10)-related cytokines was used to generate a phylogenetic tree for the class II cytokine genes. Only one IFN-a was used in this alignment because the thirteen human IFN- a subtypes have nearly identical sequences.