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Nature. 2019 Mar;567(7746):56-60. doi: 10.1038/s41586-019-0988-7. Epub 2019 Feb 27.

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

Author information

1
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
2
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
3
Institute for Molecular Engineering and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
4
Stanford Blood Center, Palo Alto, CA, USA.
5
Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA, USA.
6
Division of Biophysics, Department of Biology, University of Osnabruck, Osnabruck, Germany.
7
Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
8
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.
9
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.

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 immunostimulatory and immunosuppressive functions of IFNγ for therapeutic applications.

PMID:
30814731
PMCID:
PMC6561087
DOI:
10.1038/s41586-019-0988-7
[Indexed for MEDLINE]
Free PMC Article

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