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

• Published in: Immunity (Cambridge, Mass.) Vol. 46; no. 3; pp. 379 - 392
• Main Authors: Mendoza, Juan L., Schneider, William M., Hoffmann, Hans-Heinrich, Vercauteren, Koen, Jude, Kevin M., Xiong, Anming, Moraga, Ignacio, Horton, Tim M., Glenn, Jeffrey S., de Jong, Ype P., Rice, Charles M., Garcia, K. Christopher
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2017; Elsevier Limited; Elsevier
• Subjects: Affinity; Animals; Cell Line; Crystallization; Crystallography, X-Ray; Cytokines; Flow Cytometry; Functional plasticity; Hepatitis; Humans; In vitro methods and tests; Infections; Interferon; Interferons - immunology; Interleukins; Kinases; Ligands; Mice; Polymerase Chain Reaction; Receptors, Interferon - immunology; Receptors, Interleukin-10 - immunology; Surface Plasmon Resonance; Tyrosine; Viral infections; Yeast; λ-Interferon
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.02.017

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. [Display omitted] •The IFN-λ ternary complex provides insight into the mechanism of IL-10Rβ engagement•High-affinity IFN-λ3 elicits greater antiproliferative and antiviral activities•In vivo, an engineered IFN-λ3 has enhanced antiviral activity over the wild-type•In contrast to IFN-λs, high-affinity type I IFNs do not improve antiviral activity Using an engineered high-affinity IFN-λ, Mendoza et al. solve the structure of the IFN-λ/IFN-λR1/IL-10Rβ ternary signaling complex. The structure reveals how IL-10Rβ can act as both a cross-reactive but cytokine-specific receptor. Structure-activity relationships of engineered type I and III IFNs provide insights into enhancing interferon functional potency.