Structure of the IFNγ receptor complex guides design of biased agonists

Mendoza, Juan L.; Escalante, Nichole K.; Jude, Kevin M.; Bellon, Junel Sotolongo; Su, Leon; Horton, Tim M.; Tsutsumi, Naotaka; Berardinelli, Steven J.; Haltiwanger, Robert S.; Piehler, Jacob; Engleman, Edgar G.; Garcia, K. Christopher

doi:10.1038/s41586-019-0988-7

Structure of the IFNγ receptor complex guides design of biased agonists

Journal Article · Tue Feb 26 23:00:00 EST 2019 · Nature (London)

DOI:https://doi.org/10.1038/s41586-019-0988-7· OSTI ID:1505425

Mendoza, Juan L. ^[1]; Escalante, Nichole K. ^[2]; Jude, Kevin M. ^[3]; Bellon, Junel Sotolongo ^[4]; Su, Leon ^[3]; Horton, Tim M. ^[3]; Tsutsumi, Naotaka ^[3]; Berardinelli, Steven J. ^[5]; Haltiwanger, Robert S. ^[5]; Piehler, Jacob ^[4]; Engleman, Edgar G. ^[2]; Garcia, K. Christopher ^[3]

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.

View Accepted Manuscript (DOE)

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), Journal Name: Nature (London) Journal Issue: 7746 Vol. 567; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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