The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity

Juan L. Mendoza, William M. Schneider, Hans Heinrich Hoffmann, Koen Vercauteren, Kevin M. Jude, Anming Xiong, Ignacio Moraga, Tim M. Horton, Jeffrey S. Glenn, Ype P. de Jong, Charles M. Rice, K. Christopher Garcia (Lead / Corresponding author)

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29 Citations (Scopus)

Abstract

Type III interferons (IFN-λs) signal through a heterodimeric receptor complex composed of the IFN-λR1 subunit, specific for IFN-λs, and interleukin-10Rβ (IL-10Rβ), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rβ for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-λ variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rβ uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.

Original languageEnglish
Pages (from-to)379-392
Number of pages14
JournalImmunity
Volume46
Issue number3
Early online date21 Mar 2017
DOIs
Publication statusPublished - 21 Mar 2017

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    Mendoza, J. L., Schneider, W. M., Hoffmann, H. H., Vercauteren, K., Jude, K. M., Xiong, A., Moraga, I., Horton, T. M., Glenn, J. S., de Jong, Y. P., Rice, C. M., & Garcia, K. C. (2017). The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity. Immunity, 46(3), 379-392. https://doi.org/10.1016/j.immuni.2017.02.017