TY - JOUR
T1 - The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity
AU - Mendoza, Juan L.
AU - Schneider, William M.
AU - Hoffmann, Hans Heinrich
AU - Vercauteren, Koen
AU - Jude, Kevin M.
AU - Xiong, Anming
AU - Moraga, Ignacio
AU - Horton, Tim M.
AU - Glenn, Jeffrey S.
AU - de Jong, Ype P.
AU - Rice, Charles M.
AU - Garcia, K. Christopher
PY - 2017/3/21
Y1 - 2017/3/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015736550&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2017.02.017
DO - 10.1016/j.immuni.2017.02.017
M3 - Article
C2 - 28329704
AN - SCOPUS:85015736550
SN - 1074-7613
VL - 46
SP - 379
EP - 392
JO - Immunity
JF - Immunity
IS - 3
ER -
