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

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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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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The authors declare no competing financial interests.

Correspondence to Sergei V. Kotenko or Grant Gallagher.

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Further reading

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.