Structure of the IFNγ receptor complex guides design of biased agonists

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

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)56-60
Number of pages5
JournalNature
Volume567
Issue number7746
DOIs
Publication statusPublished - Mar 7 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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