Type I Interferon Receptors: Biochemistry and Biological Functions (2007)

The type I interferon (IFN) 2The abbreviations used are: IFN, interferon; IFNAR, type I IFN receptor; IFNGR, type II IFNγ receptor; hu, human; hCR, helical cytokine receptor; ECD, extracellular domain; FBN, fibronectin; TF, tissue factor; SD, subdomain; PDB, Protein Data Bank; IL, interleukin; aa, amino acid(s); s (sIL, sIFN), soluble; JAK, Janus kinase; STAT, signal transducers and activators of transcription. receptor (IFNAR) is comprised, as other cytokine receptors, of multiple components, in this case designated IFNAR1 and IFNAR2. However it is unique among cytokine receptors in the number of cognate ligands, including 13 IFNα subtypes, β, ω, ∊, κ, and others in some species. The type I IFN receptors are distinct from those required for the type II IFNγ (IFNGR1 and IFNGR2) and type III IFNs (IFNLR and IL10Rβ). Nevertheless, genes encoding a component of each type of IFN receptor, namely IFNAR1, IFNAR2, IFNGR2, and IL10Rβ, are located on human chromosome 21q22.1 in a cytokine receptor gene cluster, as typical of functionally related genes. Although IFNs were identified 50 years ago and the existence of IFN receptors 10 years later, it was in 1990 when the first type I IFN receptor, now designated IFNAR1, was cloned. This was achieved utilizing human gene libraries expressed in murine cells and rescue of the definitive, species specific antiviral activity of human IFNα8 (1Uze G. Lutfalla G. Gresser I. Cell. 1990; 60: 225-234Abstract Full Text PDF PubMed Scopus (513) Google Scholar). IFNAR2 cloning was achieved first by identifying a human IFN binding activity in urine, peptide sequencing, and then by gene library screening with derived oligonucleotides (2Novick D. Cohen B. Rubinstein M. Cell. 1994; 77: 391-400Abstract Full Text PDF PubMed Scopus (585) Google Scholar). It was subsequently discovered that the original cDNA encoded only one isoform of the IFNAR2 gene, which also encoded a long transmembrane isoform that transduced a signal, a truncated transmembrane isoform, and a soluble/secreted isoform (3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar) (Fig. 1A). Subsequently, the functions of the type I IFN receptors have been elucidated with respect to ligand interaction, mechanisms of signal transduction, and biological responses. The pioneering studies that discovered IFNARs and their mechanisms of actions in vitro have been largely validated in vivo using genetargeted mice. This body of work has highlighted the important roles of IFNARs in mediating type I IFN responses in hemopoiesis and innate and acquired immunity to infection and cancer. However, IFNs elicit many biological effects that can even be opposite in different cell types. For example, type I IFN inhibits proliferation and is proapoptotic for many cell types (4Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2372) Google Scholar), yet it prolongs the survival of memory T cells (5Tough D.F. Sun S. Zhang X. Sprent J. Immunol. Rev. 1999; 170: 39-47Crossref PubMed Scopus (93) Google Scholar). Understanding the function of the IFNAR complex will elucidate how such a diversity of biological outcomes is generated. The IFNAR genes encode multiple isoforms that contribute to the potential complexity of the functional receptor (2Novick D. Cohen B. Rubinstein M. Cell. 1994; 77: 391-400Abstract Full Text PDF PubMed Scopus (585) Google Scholar, 3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar, 6Owczarek C.M. Hwang S.Y. Holland K.A. Gulluyan L.M. Tavaria M. Weaver B. Reich N.C. Kola I. Hertzog P.J. J. Biol. Chem. 1997; 272: 23865-23870Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Two splice variants of IFNAR1 have been identified in cell lines (7Abramovich C. Ratovitski E. Lundgren E. Revel M. FEBS Lett. 1994; 338: 295-300Crossref PubMed Scopus (29) Google Scholar, 8Cook J.R. Cleary C.M. Mariano T.M. Izotova L. Pestka S. J. Biol. Chem. 1996; 271: 13448-13453Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). However, subsequent bioinformatic analyses of splice variants in expressed sequence tag (EST) data bases and rapid amplification of cDNA ends (3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar′-RACE) analyses from normal cells identified only one isoform, suggesting that the former are either artifacts or aberrant transcripts found only in particular tumor cell lines. 3S. A. Samarajiwa and P. J. Hertzog, unpublished data. In contrast, four IFNAR2 transcripts encoding three isoforms are generated from the same gene by exon skipping, alternative splicing, and differential usage of polyadenylation sites (3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar) (Fig. 1A) These transcripts encode a long trans-membrane IFNAR2c, a short transmembrane IFNAR2b chain, and a soluble sIFNAR2a chain. Transfection of human IFNAR1 and IFNAR2c, but not IFNAR2b, reconstituted the antiviral IFN response (9Cohen B. Novick D. Barak S. Rubinstein M. Mol. Cell. Biol. 1995; 15: 4208-4214Crossref PubMed Scopus (152) Google Scholar). This is consistent with data, at least in sarcomas, that IFNAR2b may act as a dominant negative regulator of IFN responses (10Gazziola C. Cordani N. Carta S. De Lorenzo E. Colombatti A. Perris R. Int. J. Oncol. 2005; 26: 129-140PubMed Google Scholar) (Fig. 1B). The mouse has been the primary model for pathophysiological studies of IFNs due to the capability of generating knockout mice, which can demonstrate cause-and-effect associations in vivo. The mouse has a comparable type I IFN system to human with multiple ligands (α, β, ∊, etc.) and Ifnar1 and Ifnar2 genes (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar, 12Hardy M.P. Sanij E.P. Hertzog P.J. Owczarek C.M. Mamm. Genome. 2003; 14: 105-118Crossref PubMed Scopus (15) Google Scholar). No IFNAR2b chain has been identified in mouse, but two transcripts capable of encoding soluble isoforms (sIfnar2a and sIfnar2a′) are generated by differential splicing. The more abundant 1.5-kb sIfnar2a transcript encodes the complete IFNAR2 extracellular domain and reads through the splice site on the exon 7–7′ boundary producing a transcript encoding 12 unique and mostly hydrophobic C-terminal residues (6Owczarek C.M. Hwang S.Y. Holland K.A. Gulluyan L.M. Tavaria M. Weaver B. Reich N.C. Kola I. Hertzog P.J. J. Biol. Chem. 1997; 272: 23865-23870Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The sIfnar2a′ minor transcript is generated from a transcript missing 128 nucleotides after codon 236 of the Ifnar2 cDNA. This isoform originates by skipping the transmembrane-encoding exon 8, leading to a frameshift forming a stop codon that generates a transcript capable of producing a soluble receptor with 11 unique C-terminal amino acids (Fig. 1A). The transmembrane and soluble Ifnar2 transcripts are differentially regulated based on Northern blot analyses of expression in murine tissues. Ratios of tmIfnar2c:sIfnar2a range from >10:1 in some tissues to ∼1:1 in hemopoietic tissues (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar). Analysis of the 5′ flanking region of Ifnar2 using promoter reporter constructs identified three regulatory regions that confer basal expression, inducible expression by IFNα + IFNγ, and a negative regulatory region (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar, 12Hardy M.P. Sanij E.P. Hertzog P.J. Owczarek C.M. Mamm. Genome. 2003; 14: 105-118Crossref PubMed Scopus (15) Google Scholar, 13Hardy M.P. Hertzog P.J. Owczarek C.M. Biochem. J. 2002; 365: 355-367Crossref PubMed Google Scholar). Structure-Function Relationships—Studies of type I IFN receptors prior to their cloning have indicated that most cell types bind IFNs, with large variation in the number of binding sites (200–10,000/cell) and binding affinities. Scatchard analyses of binding usually identify two types of binding sites of low (μm) and high affinity (nm–pm) (14Langer J.A. Pestka S. Immunol. Today. 1988; 9: 393-400Abstract Full Text PDF PubMed Scopus (191) Google Scholar). This pattern of binding is consistent with a multicomponent receptor containing a high affinity binding chain (often called the α or primary binding chain) and a β or signal-transducing chain that has low intrinsic ligand binding affinity and converts the affinity of interaction of ligand with α chain from moderate (nm) to high affinity (pm) (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar). Recently, elegant studies using recombinant IFNAR extracellular domains (ECDs) tethered to lipid membranes have clearly demonstrated that various type I IFNs bind to IFNAR2 with Kd values mostly in the nm range (from 0.1 to 1000 nm) and bind to IFNAR1 with Kd mostly in the μm range (from 0.05 to 10 μm) (16Jaks E. Gavutis M. Uze G. Martal J. Piehler J. J. Mol. Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar). IFNAR Structures—IFNAR1 and IFNAR2 belong to the class II helical cytokine receptor (hCR) family, which includes the receptor for type II IFN, tissue factor (TF), and IL10Rβ (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar). Members of the class II hCR family contain tandem ∼100 amino acid (aa) domains with a predicted topology analogous to the Ig constant domain (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar). The ECD of huIFNAR1, comprising 409 aa (403 in the murine form) contains four subdomains, referred to as SD1–SD4, each housing one fibronectin (FBN-III-like) domain (Fig. 2). SD1 contains conserved residues implicated in binding membrane glycosphingolipids (17Ghislain J. Lingwood C.A. Fish E.N. J. Immunol. 1994; 153: 3655-3663PubMed Google Scholar). SD1–SD3 appears to house the ligand binding domain; SD4 is essential for ternary complex formation (18Lamken P. Gavutis M. Peters I. Van der Heyden J. Uze G. Piehler J. J. Mol. Biol. 2005; 350: 476-488Crossref PubMed Scopus (48) Google Scholar). The SD1-SD2 pair is structurally similar to the SD3-SD4 pair with characteristic disulfide-bonding cysteine pairs (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar) and 50% sequence homology (19Uze G. Lutfalla G. Mogensen K.E. J. Interferon Cytokine Res. 1995; 15: 3-26Crossref PubMed Scopus (232) Google Scholar). NMR has been used to model huIFNAR2 structure and its interaction with huIFNα2 (20Chill J.H. Quadt S.R. Levy R. Schreiber G. Anglister J. Structure (Lond.). 2003; 11: 791-802Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), which has similarities to and differences from the resolved crystal structures of two members of the class II hCR group, TF (21Harlos K. Martin D.M. O'Brien D.P. Jones E.Y. Stuart D.I. Polikarpov I. Miller A. Tuddenham E.G. Boys C.W. Nature. 1994; 370: 662-666Crossref PubMed Scopus (215) Google Scholar) and IFNGR (22Walter M.R. Windsor W.T. Nagabhushan T.L. Lundell D.J. Lunn C.A. Zauodny P.J. Narula S.K. Nature. 1995; 376: 230-235Crossref PubMed Scopus (360) Google Scholar). As predicted for class II hCR receptors (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar), all three proteins have two FBN-III domains with Ig-like folding topology and two conserved disulfide bonds (22Walter M.R. Windsor W.T. Nagabhushan T.L. Lundell D.J. Lunn C.A. Zauodny P.J. Narula S.K. Nature. 1995; 376: 230-235Crossref PubMed Scopus (360) Google Scholar, 23Runkel L. deDios C. Karpusas M. Betzenhauser M. Muldowney C. Zafari M. Benjamin C.D. Miller S. Hochman P.S. Whitty A. Biochemistry. 2000; 39: 2538-2551Crossref PubMed Scopus (74) Google Scholar, 24Cajean-Feroldi C. Nosal F. Nardeux P.C. Gallet X. Guymarho J. Baychelier F. Sempe P. Tovey M.G. Escary J.L. Eid P. Biochemistry. 2004; 43: 12498-12512Crossref PubMed Scopus (33) Google Scholar). However, unlike TF and IFNGR, which show a conserved interdomain angle of ∼120° (21Harlos K. Martin D.M. O'Brien D.P. Jones E.Y. Stuart D.I. Polikarpov I. Miller A. Tuddenham E.G. Boys C.W. Nature. 1994; 370: 662-666Crossref PubMed Scopus (215) Google Scholar, 22Walter M.R. Windsor W.T. Nagabhushan T.L. Lundell D.J. Lunn C.A. Zauodny P.J. Narula S.K. Nature. 1995; 376: 230-235Crossref PubMed Scopus (360) Google Scholar), huIFNAR2 has an interdomain angle approximating 90° (20Chill J.H. Quadt S.R. Levy R. Schreiber G. Anglister J. Structure (Lond.). 2003; 11: 791-802Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) (Fig. 2). Based on the prediction that type I IFNs have an interaction surfaces for each receptor on opposing sides of the ligand (23Runkel L. deDios C. Karpusas M. Betzenhauser M. Muldowney C. Zafari M. Benjamin C.D. Miller S. Hochman P.S. Whitty A. Biochemistry. 2000; 39: 2538-2551Crossref PubMed Scopus (74) Google Scholar) and on information regarding the locations of amino acids implicated in ligand binding on both IFNAR1 and IFNAR2, a three-dimensional model for the ligand-bound human type I IFN receptor complex has been proposed (24Cajean-Feroldi C. Nosal F. Nardeux P.C. Gallet X. Guymarho J. Baychelier F. Sempe P. Tovey M.G. Escary J.L. Eid P. Biochemistry. 2004; 43: 12498-12512Crossref PubMed Scopus (33) Google Scholar). This model predicts that upon ligand binding, the N-terminal FBN-III domain of IFNAR1 forms a lid over the bound ligand (24Cajean-Feroldi C. Nosal F. Nardeux P.C. Gallet X. Guymarho J. Baychelier F. Sempe P. Tovey M.G. Escary J.L. Eid P. Biochemistry. 2004; 43: 12498-12512Crossref PubMed Scopus (33) Google Scholar). However, this prediction fails to consider the residues of IFNAR1 implicated in binding membrane glycosphingolipids (17Ghislain J. Lingwood C.A. Fish E.N. J. Immunol. 1994; 153: 3655-3663PubMed Google Scholar) so that the N terminus of IFNAR1 may fold toward the membrane, stabilizing the molecule before or after ligand binding. IFNAR-Ligand Interaction—The binding site of IFNα2 on IFNAR1 has been predicted from site-directed mutagenesis (24Cajean-Feroldi C. Nosal F. Nardeux P.C. Gallet X. Guymarho J. Baychelier F. Sempe P. Tovey M.G. Escary J.L. Eid P. Biochemistry. 2004; 43: 12498-12512Crossref PubMed Scopus (33) Google Scholar, 25Lamken P. Lata S. Gavutis M. Piehler J. J. Mol. Biol. 2004; 341: 303-318Crossref PubMed Scopus (108) Google Scholar) and epitope mapping with an anti-IFNAR1-neutralizing antibody (26Eid P. Langer J.A. Bailly G. Lejealle R. Guymarho J. Tovey M.G. Eur. Cytokine Netw. 2000; 11: 560-573PubMed Google Scholar) (Fig. 2), albeit the latter may be inaccurate because of steric hindrances. Residues involved in ligand binding are found on the three membrane-distal FBN-III SD domains. Residues 69VY70 have been identified as the key residues in IFNAR1 recognition by a neutralizing monoclonal antibody (26Eid P. Langer J.A. Bailly G. Lejealle R. Guymarho J. Tovey M.G. Eur. Cytokine Netw. 2000; 11: 560-573PubMed Google Scholar) and thus proposed to influence IFNα2 binding (24Cajean-Feroldi C. Nosal F. Nardeux P.C. Gallet X. Guymarho J. Baychelier F. Sempe P. Tovey M.G. Escary J.L. Eid P. Biochemistry. 2004; 43: 12498-12512Crossref PubMed Scopus (33) Google Scholar). A number of other surface-exposed, aromatic residues within the surrounding region have also been demonstrated to aid IFNα2 binding (24Cajean-Feroldi C. Nosal F. Nardeux P.C. Gallet X. Guymarho J. Baychelier F. Sempe P. Tovey M.G. Escary J.L. Eid P. Biochemistry. 2004; 43: 12498-12512Crossref PubMed Scopus (33) Google Scholar) (Fig. 2). Studies from our laboratory and others suggest that IFNAR1 is for and is for the differential recognition of the IFN ligands (16Jaks E. Gavutis M. Uze G. Martal J. Piehler J. J. Mol. Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar, P. Gavutis M. Peters I. Van der Heyden J. Uze G. Piehler J. J. Mol. Biol. 2005; 350: 476-488Crossref PubMed Scopus (48) Google Scholar, M. Mogensen K.E. Uze G. J. Mol. Biol. PubMed Scopus Google Scholar, J. Schreiber G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar). studies have the residues of IFNAR2 involved in ligand with IFNα2 and (20Chill J.H. Quadt S.R. Levy R. Schreiber G. Anglister J. Structure (Lond.). 2003; 11: 791-802Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 25Lamken P. Lata S. Gavutis M. Piehler J. J. Mol. Biol. 2004; 341: 303-318Crossref PubMed Scopus (108) Google Scholar, M. Mogensen K.E. Uze G. J. Mol. Biol. PubMed Scopus Google Scholar, J. Schreiber G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar) (Fig. 2). the ligand binding site of huIFNAR2 is largely of hydrophobic amino acids (20Chill J.H. Quadt S.R. Levy R. Schreiber G. Anglister J. Structure (Lond.). 2003; 11: 791-802Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, K. Martin D.M. O'Brien D.P. Jones E.Y. Stuart D.I. Polikarpov I. Miller A. Tuddenham E.G. Boys C.W. Nature. 1994; 370: 662-666Crossref PubMed Scopus (215) Google Scholar, 22Walter M.R. Windsor W.T. Nagabhushan T.L. Lundell D.J. Lunn C.A. Zauodny P.J. Narula S.K. Nature. 1995; 376: 230-235Crossref PubMed Scopus (360) Google Scholar) (Fig. 2). the of the IFNAR2 ligand binding domain are three conserved residues and and also IFNα2 binding M. Mogensen K.E. Uze G. J. Mol. Biol. PubMed Scopus Google Scholar, J. Schreiber G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar). These residues are predicted by NMR to an and largely hydrophobic on the of IFNAR2 (Fig. (20Chill J.H. Quadt S.R. Levy R. Schreiber G. Anglister J. Structure (Lond.). 2003; 11: 791-802Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). The interaction of is predicted to be different from IFNAR2 residues and with minor from and (Fig. J. Schreiber G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar). It appears that the sequence differences type I IFNs in different binding with each IFNAR chain and biological (16Jaks E. Gavutis M. Uze G. Martal J. Piehler J. J. Mol. Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar). cytokine receptors are in body and cytokine activity and R. J. 5: PubMed Scopus Google Scholar). IFNAR2 receptors are in urine, and the of both and (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar, D. Cohen B. Rubinstein M. FEBS Lett. PubMed Scopus Google Scholar). In vitro studies demonstrate that a soluble IFNAR2 can also be generated by of transmembrane IFNAR2 by in response to IFNs and other D. A. 2004; PubMed Scopus Google Scholar), but is in vivo for this Nevertheless, is a in the receptor system the soluble is generated both by alternative and by by 10 and P.J. J. S. J. Interferon Cytokine Res. 2005; PubMed Scopus Google Scholar). Although a function for the soluble IFNAR2 isoform has not yet been in vitro have demonstrated that sIFNAR2a can act either as an or (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar). can IFN in normal in primary from mice, sIFNAR2a can bind IFNα or and an signal (Fig. 1B). In soluble IFNAR2 was to antiviral activity in vitro Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus (29) Google Scholar). over the soluble receptor are more to suggesting that high of the sIFNAR2a receptor can IFN in vivo. A. M. C. M. and P. J. Hertzog, unpublished data. or actions of soluble may be by the of which is the of signal by and P.J. J. S. J. Interferon Cytokine Res. 2005; PubMed Scopus Google Scholar, M.P. M. J.F. J.H. C.D. Sprent J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). also have a as bound sIFNAR2a the of and the activity in a tumor model K. R. J. Interferon Cytokine Res. 2004; PubMed Scopus Google Scholar). and type I IFN receptor, typical of class II hCR, intrinsic activity and thus on Janus to receptors and signal such as after receptor IFNAR1 is with K. Mol. Cell. 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In the case of and the chain, this is the of because is expressed on most but the transmembrane of expression S. 2002; PubMed Scopus Google Scholar). have demonstrated in vitro that sIFNAR2a can bind IFNα or and a signal through IFNAR1 (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar). our using sIFNAR2a suggest that high of sIFNAR2a may act as in Although more of in the IFN system is it a for alternative tissues and and most cell lines transcripts for IFNAR1 and both soluble and transmembrane isoforms of IFNAR2 (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar, 12Hardy M.P. Sanij E.P. Hertzog P.J. Owczarek C.M. Mamm. Genome. 2003; 14: 105-118Crossref PubMed Scopus (15) Google Scholar, 13Hardy M.P. Hertzog P.J. Owczarek C.M. Biochem. J. 2002; 365: 355-367Crossref PubMed Google Scholar) and thus bind and to of expression in different tissues and cells that is some differential expression of IFNAR1 and IFNAR2, with IFNAR1 more and IFNAR2 more These studies to be validated by other with that the of IFNAR at the cell to a of the of the IFNAR receptor on different cell types and with in Ifnar1 have demonstrated that this component is essential for responses to multiple IFNα as as S.Y. Hertzog P.J. Holland K.A. J.A. Whitty G. I. Kola I. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar, U. U. S. J. M. 1994; PubMed Scopus Google Scholar). of has demonstrated the of Ifnar1 for survival most and and T responses and as a have also generated with a in the Ifnar2 gene that a similar to Ifnar1 in their to and but were distinct in their T cell J. Hertzog, B. C. M. M. J. S. and J. unpublished data. The differences in were in their in hemopoiesis and in the of R. Zhang D. Schreiber K. D.J. Hertzog P.J. Nat. 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This is an in that it has low amino acid homology to IFNAR1 or IFNAR2 but has a based on and is a of the antiviral activity of a range of type I IFNs the species of The IFNAR complex is among cytokine receptors in mediating by more different but related type I IFN This system has been in the of the which is for genes involved in the characteristic antiviral However data that many more alternative are by IFNAR This diversity of may how IFNs complex biological responses. has been in the structure of the receptor However, more studies and of the potential in receptor that which elicit are to elucidate how the different biological of type I IFNs can be regulated by the