Structure of the IFNγ receptor complex guides design of biased agonists.

Nature
Juan L MendozaK Christopher Garcia

Abstract

The cytokine interferon-γ (IFNγ) is a central coordinator of innate and adaptive immunity, but its highly pleiotropic actions have diminished its prospects for use as an immunotherapeutic agent. Here, we took a structure-based approach to decoupling IFNγ pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNγ receptor IFNγR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNγ-IFNγR1-IFNγR2 signalling complex at 3.25 Å resolution. The structure reveals the mechanism underlying deficits in IFNγ responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNγR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNγ variants to tune IFNγ receptor signalling output. Unexpectedly, we found that several partial IFNγ agonists exhibited biased gene-expression profiles. These biased agonists retained the ability to induce upregulation of major histocompatibility complex class I antigen expression, but exhibited impaired induction of programmed death-ligand 1 expression in a wide range of human cancer cell lines, offering a route to decoupling immunostimulator...Continue Reading

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Citations

Nov 21, 2019·Nature Immunology·Franck J BarratLionel B Ivashkiv
Jun 9, 2020·Frontiers in Pharmacology·Wenqiang CuiShuguang Yuan
Jun 17, 2020·Proceedings of the National Academy of Sciences of the United States of America·Preeti SharmaDavid M Kranz
Jul 24, 2020·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Ailin ElyasiAllison B Reiss
Jun 12, 2019·Experimental Biology and Medicine·Qianqian MingVincent C Luca
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Oct 3, 2020·Biomarker Research·Dragica JorgovanovicYi Zhang
Jan 10, 2020·EMBO Molecular Medicine·Thomas KammertoensMatthias Leisegang
Apr 11, 2020·Head & Neck·Maxwell Y Lee, Clint T Allen
Jan 2, 2021·Proceedings of the National Academy of Sciences of the United States of America·Lu CuiGerlinde Wernig
Dec 8, 2020·Frontiers in Immunology·Mark R Walter
Jun 23, 2021·Nature Reviews. Immunology·Angela M GocherDario A A Vignali
Sep 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Patrick BinderUlrich S Schwarz

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Methods Mentioned

BETA
PCR
glycosylation
surface plasmon resonance
size-exclusion chromatography
AmpliSeq
flow cytometry
density gradient centrifugation
PCA
fluorescence microscopy
genotyping

Software Mentioned

MATLAB
Proteome Discoverer
Phenix
Coot
GraphPad Prism
Phaser
Xcalibur
Ion Torrent Suite

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