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Title: Structure of the IFNγ receptor complex guides design of biased agonists

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. 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.

Authors:
 [1];  [2];  [3];  [4];  [3];  [3];  [3];  [5];  [5];  [4];  [2];  [3]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States); Univ. of Chicago, Chicago, IL (United States)
  2. Stanford Blood Center, Palo Alto, CA (United States); Stanford Univ., Palo Alto, CA (United States)
  3. Stanford Univ. School of Medicine, Stanford, CA (United States)
  4. Univ. of Osnabruck, Osnabruck (Germany)
  5. Univ. of Georgia, Athens, GA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1505425
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 567; Journal Issue: 7746; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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., and Garcia, K. Christopher. Structure of the IFNγ receptor complex guides design of biased agonists. United States: N. p., 2019. Web. doi:10.1038/s41586-019-0988-7.
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. Structure of the IFNγ receptor complex guides design of biased agonists. United States. doi:10.1038/s41586-019-0988-7.
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., and Garcia, K. Christopher. Wed . "Structure of the IFNγ receptor complex guides design of biased agonists". United States. doi:10.1038/s41586-019-0988-7. https://www.osti.gov/servlets/purl/1505425.
@article{osti_1505425,
title = {Structure of the IFNγ receptor complex guides design of biased agonists},
author = {Mendoza, Juan L. and Escalante, Nichole K. and Jude, Kevin M. and Bellon, Junel Sotolongo and Su, Leon and Horton, Tim M. and Tsutsumi, Naotaka and Berardinelli, Steven J. and Haltiwanger, Robert S. and Piehler, Jacob and Engleman, Edgar G. and Garcia, K. Christopher},
abstractNote = {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.},
doi = {10.1038/s41586-019-0988-7},
journal = {Nature (London)},
number = 7746,
volume = 567,
place = {United States},
year = {2019},
month = {2}
}

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    Cytokine Therapeutics in Cancer Immunotherapy: Design and Development
    journal, June 2019


    Cytokine Therapeutics in Cancer Immunotherapy: Design and Development
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