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 language | English |
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Pages (from-to) | 379-392 |
Number of pages | 14 |
Journal | Immunity |
Volume | 46 |
Issue number | 3 |
Early online date | 21 Mar 2017 |
DOIs | |
Publication status | Published - 21 Mar 2017 |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases
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Moraga Gonzalez, Ignacio
- Cell Signalling and Immunology - Reader (Teaching and Research)
Person: Academic