Structure of the IFN[gamma] receptor complex guides design of biased agonists

The cytokine interferon-[gamma] (IFN[gamma]) 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 IFN[gamma] pleiotropy. We engineered a...

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Published inNature (London) Vol. 567; no. 7746; pp. 56 - 111
Main Authors Mendoza, Juan L, Escalante, Nichole K, Jude, Kevin M, Sotolongo Bellon, Junel, Su, Leon, Horton, Tim M, Tsutsumi, Naotaka
Format Journal Article
LanguageEnglish
Published Nature Publishing Group 01.03.2019
Subjects
Agonists (Biochemistry)
Antigens
Bacterial infections
Biological response modifiers
Crystal structure
Cytokines
Genes
Immunologic factors
Immunotherapy
Interferon
Interferon gamma
Major histocompatibility complex
Physiological research
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Summary:The cytokine interferon-[gamma] (IFN[gamma]) 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 IFN[gamma] pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFN[gamma] receptor IFN[gamma]R1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFN[gamma]-IFN[gamma]R1-IFN[gamma]R2 signalling complex at 3.25 Å resolution. The structure reveals the mechanism underlying deficits in IFN[gamma] responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFN[gamma]R2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFN[gamma] variants to tune IFN[gamma] receptor signalling output. Unexpectedly, we found that several partial IFN[gamma] 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 immunostimulatory and immunosuppressive functions of IFN[gamma] for therapeutic applications.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-0988-7