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IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex

Nature Immunology volume 4, pages 69–77 (2003)Cite this article

Abstract

We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-λ1 (IFN-λ1), IFN-λ2 and IFN-λ3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-λ mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-λ proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-λR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases–signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.

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Figure 1: CRF2-12.
Figure 2: Expression pattern of CRF2-12 mRNA.
Figure 3: IFN-λs.
Figure 4: IFN-λs expression.
Figure 5: MHC class I antigen expression, ligand binding and EMSA.
Figure 6: Ligand cross-linking.
Figure 7: STAT activation performed on human cells.
Figure 8: Biological activities.

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References

  1. Kotenko, S.V. The family of IL10-related cytokines and their receptors: related, but to what extent? Cytokine Growth Factor Rev. 13, 223–240 (2002).

    Article  CAS  Google Scholar 

  2. Kotenko, S.V. & Pestka, S. Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 19, 2557–2565 (2000).

    Article  CAS  Google Scholar 

  3. Dumoutier, L. & Renauld, J.C. Viral and cellular interleukin-10 (IL-10)-related cytokines: from structures to functions. Eur. Cytokine Netw. 13, 5–15 (2002).

    CAS  PubMed  Google Scholar 

  4. Fickenscher, H. et al. The interleukin-10 family of cytokines. Trends Immunol. 23, 89–96 (2002).

    Article  CAS  Google Scholar 

  5. Pestka, S. The human interferon α species and hybrid proteins. Semin. Oncol. 24 (Suppl. 9) 4–17 (1997).

    CAS  Google Scholar 

  6. LaFleur, D.W. et al. Interferon-κ, a novel type I interferon expressed in human keratinocytes. J. Biol. Chem. 276, 39765–39771 (2001).

    Article  CAS  Google Scholar 

  7. Conklin, D.C., Grant, F.J., Rixon, M.W. & Kindsvogel, W. Interferon-ε. U.S. Patent 6329175 (2002).

  8. Moore, K.W., de Waal, M.R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  Google Scholar 

  9. Levy, D.E. & Garcia-Sastre, A. The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion. Cytokine Growth Factor Rev. 12, 143–156 (2001).

    Article  CAS  Google Scholar 

  10. Samuel, C.E. Antiviral actions of interferons. Clin. Microbiol. Rev. 14, 778–809 (2001).

    Article  CAS  Google Scholar 

  11. Biron, C.A. Interferons α and β as immune regulators–a new look. Immunity 14, 661–664 (2001).

    Article  CAS  Google Scholar 

  12. Le Bon, A. & Tough, D.F. Links between innate and adaptive immunity via type I interferon. Curr. Opin. Immunol. 14, 432–436 (2002).

    Article  CAS  Google Scholar 

  13. Prejean, C. & Colamonici, O.R. Role of the cytoplasmic domains of the type I interferon receptor subunits in signaling. Semin. Cancer. Biol. 10, 83–92 (2000).

    Article  CAS  Google Scholar 

  14. Domanski, P. & Colamonici, O.R. The type-I interferon receptor. The long and short of it. Cytokine Growth Factor Rev. 7, 143–151 (1996).

    Article  CAS  Google Scholar 

  15. Darnell, J.E. Jr., Kerr, I.M. & Stark, G.R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421 (1994).

    Article  CAS  Google Scholar 

  16. Steinhoff, U. et al. Antiviral protection by vesicular stomatitis virus-specific antibodies in α/β interferon receptor-deficient mice. J. Virol. 69, 2153–2158 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).

    Article  CAS  Google Scholar 

  18. Hwang, S.Y. et al. A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons α and β and alters macrophage responses. Proc. Natl. Acad. Sci. USA 92, 11284–11288 (1995).

    Article  CAS  Google Scholar 

  19. Lu, B. et al. Targeted disruption of the interferon-γ receptor 2 gene results in severe immune defects in mice. Proc. Natl. Acad. Sci. USA 95, 8233–8238 (1998).

    Article  CAS  Google Scholar 

  20. Angel, J., Franco, M.A., Greenberg, H.B. & Bass, D. Lack of a role for type I and type II interferons in the resolution of rotavirus-induced diarrhea and infection in mice. J. Interferon Cytokine Res. 19, 655–659 (1999).

    Article  CAS  Google Scholar 

  21. Kotenko, S.V. et al. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 16, 5894–5903 (1997).

    Article  CAS  Google Scholar 

  22. Wolk, K., Kunz, S., Asadullah, K. & Sabat, R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J. Immunol. 168, 5397–5402 (2002).

    Article  CAS  Google Scholar 

  23. Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).

    Article  CAS  Google Scholar 

  24. Kotenko, S.V. et al. Other kinases can substitute for Jak2 in signal transduction by interferon-γ. J. Biol. Chem. 271, 17174–17182 (1996).

    Article  CAS  Google Scholar 

  25. Kotenko, S.V. et al. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rβ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol. Chem. 276, 2725–2732 (2001).

    Article  CAS  Google Scholar 

  26. Siegal, F.P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999).

    Article  CAS  Google Scholar 

  27. Knappe, A., Hor, S., Wittmann, S. & Fickenscher, H. Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74, 3881–3887 (2000).

    Article  CAS  Google Scholar 

  28. Levy, D.E. . Whence interferon? Variety in the production of interferon in response to viral infection. J. Exp. Med. 195, 15–18 (2002).

    Article  Google Scholar 

  29. Kotenko, S.V., Izotova, L.S., Mirochnitchenko, O.V., Lee, C. & Pestka, S. The intracellular domain of interferon-receptor 2c (IFN-R2c) chain is responsible for Stat activation. Proc. Natl. Acad. Sci. USA 96, 5007–5012 (1999).

    Article  CAS  Google Scholar 

  30. Nadeau, O.W. et al. The proximal tyrosines of the cytoplasmic domain of the β chain of the type I interferon receptor are essential for signal transducer and activator of transcription (Stat) 2 activation. Evidence that two Stat2 sites are required to reach a threshold of interferon α-induced Stat2 tyrosine phosphorylation that allows normal formation of interferon-stimulated gene factor 3. J. Biol. Chem. 274, 4045–4052 (1999).

    Article  CAS  Google Scholar 

  31. Wagner, T.C. et al. Interferon signaling is dependent on specific tyrosines located within the intracellular domain of IFNAR2c. Expression of IFNAR2c tyrosine mutants in U5A cells. J. Biol. Chem. 277, 1493–1499 (2002).

    Article  CAS  Google Scholar 

  32. Goldman, L.A., Cutrone, E.C., Kotenko, S.V., Krause, C.D. & Langer, J.A. Modifications of vectors pEF-BOS, pcDNA1 and pcDNA3 result in improved convenience and expression. Biotechniques 21, 1013–1015 (1996).

    Article  CAS  Google Scholar 

  33. Kotenko, S.V., Saccani, S., Izotova, L.S., Mirochnitchenko, O.V. & Pestka, S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc. Natl. Acad. Sci. USA 97, 1695–1700 (2000).

    Article  CAS  Google Scholar 

  34. Li, B.L., Langer, J.A., Schwartz, B. & Pestka, S. Creation of phosphorylation sites in proteins: construction of a phosphorylatable human interferon α. Proc. Natl. Acad. Sci. USA 86, 558–562 (1989).

    Article  CAS  Google Scholar 

  35. Soh, J. et al. Identification of a yeast artificial chromosome clone encoding an accessory factor for the human interferon γ receptor: evidence for multiple accessory factors. Proc. Natl. Acad. Sci. USA 90, 8737–8741 (1993).

    Article  CAS  Google Scholar 

  36. Barnstable, C.J. et al. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis. Cell 14, 9–20 (1978).

    Article  CAS  Google Scholar 

  37. Kotenko, S.V. et al. Interaction between the components of the interferon γ receptor complex. J. Biol. Chem. 270, 20915–20921 (1995).

    Article  CAS  Google Scholar 

  38. Reich, N. et al. Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc. Natl. Acad. Sci. USA 84, 6394–6398 (1987).

    Article  CAS  Google Scholar 

  39. Gallagher, G. et al. Cloning, expression and initial characterization of interleukin-19 (IL- 19), a novel homologue of human interleukin-10 (IL-10). Genes Immun. 1, 442–450 (2000).

    Article  CAS  Google Scholar 

  40. Pestka, S. et al. Introduction of protein kinase recognition sites into proteins: a review of their preparation, advantages, and applications. Protein Expr. Purif. 17, 203–214 (1999).

    Article  CAS  Google Scholar 

  41. Kotenko, S.V. et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol. 166, 7096–7103 (2001).

    Article  CAS  Google Scholar 

  42. Yu, S.H. et al. Intrahepatic mRNA expression of interferon-inducible antiviral genes in liver diseases: dsRNA-dependent protein kinase overexpression and RNase L inhibitor suppression in chronic hepatitis C. Hepatology 32, 1089–1095 (2000).

    Article  CAS  Google Scholar 

  43. Tian, Z., Shen, X., Feng, H. & Gao, B. IL-1 β attenuates IFN-α β-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway. J. Immunol. 165, 3959–3965 (2000).

    Article  CAS  Google Scholar 

  44. Familletti, P.C., Rubinstein, S. & Pestka, S. A convenient and rapid cytopathic effect inhibition assay for interferon. Meth. Enzymol. 78, 387–394 (1981).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported in part by United States Public Health Services grant RO1 AI51139 from the National Institute of Allergy and Infectious Diseases and by American Heart Association grant AHA number 0245131N (to S.V.K) and by startup funds from the Department of Oral Biology, NJDS (to G.G.). We are thankful to S. Pestka for providing 16-9 hamster cells and other valuable reagents, and P. Liang for HaCaT cells.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, UMDNJ – New Jersey Medical School, Newark, 07103, NJ, USA

    Sergei V. Kotenko, Vitaliy V. Baurin, Anita Lewis-Antes, Meiling Shen & Nital K. Shah

  2. Department of Oral Biology, UMDNJ – New Jersey Dental School, Newark, 07103, NJ, USA

    Grant Gallagher

  3. Department of Molecular Genetics Microbiology and Immunology, UMDNJ – Robert Wood Johnson Medical School, Piscataway, 08854, NJ, USA

    Jerome A. Langer

  4. Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, 20892, MD, USA

    Faruk Sheikh, Harold Dickensheets & Raymond P. Donnelly

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Kotenko, S., Gallagher, G., Baurin, V. et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4, 69–77 (2003). https://doi.org/10.1038/ni875

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