Structure of the IFNγ receptor complex guides design of biased agonists
- Stanford Univ. School of Medicine, Stanford, CA (United States); Univ. of Chicago, Chicago, IL (United States)
- Stanford Blood Center, Palo Alto, CA (United States); Stanford Univ., Palo Alto, CA (United States)
- Stanford Univ. School of Medicine, Stanford, CA (United States)
- Univ. of Osnabruck, Osnabruck (Germany)
- Univ. of Georgia, Athens, GA (United States)
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. Here, 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.
- Research Organization:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Organization:
- USDOE
- Grant/Contract Number:
- AC02-76SF00515
- OSTI ID:
- 1505425
- Journal Information:
- Nature (London), Vol. 567, Issue 7746; ISSN 0028-0836
- Publisher:
- Nature Publishing GroupCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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