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

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