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

Research output: Contribution to journalArticle

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
JournalImmunity
Volume46
Issue number3
Pages (from-to)379-392
Number of pages14
ISSN1074-7613
DOIs
Publication statusPublished - 21-Mar-2017

Keywords

  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • Flow Cytometry
  • Humans
  • Interferons/immunology
  • Mice
  • Polymerase Chain Reaction
  • Receptors, Interferon/immunology
  • Receptors, Interleukin-10/immunology
  • Surface Plasmon Resonance

Cite this