Abstract

Type III interferons (IFN-?s) signal through a heterodimeric receptor complex composed of the IFN-?R1 subunit, specific for IFN-?s, and interleukin-10Rß (IL-10Rß), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rß for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-? variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rß 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.

View details for DOI 10.1016/j.immuni.2017.02.017

View details for PubMedID 28329704