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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Journal | Immunity |
Volume | 46 |
Issue number | 3 |
Pages (from-to) | 379-392 |
Number of pages | 14 |
ISSN | 1074-7613 |
DOIs | |
Publication status | Published - 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