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

Mendoza JL, Escalante NK, Jude KM, Sotolongo Bellon J, Su L, Horton TM, Tsutsumi N, Berardinelli SJ, Haltiwanger RS, Piehler J, Engleman EG, Garcia KC
Nature 567 56-60 (2019)
Cited: 58 times
EuropePMC logo PMID: 30814731

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.

Reviews - 6e3k mentioned but not cited (1)

  1. The Role of Structure in the Biology of Interferon Signaling. Walter MR. Front Immunol 11 606489 (2020)

Articles - 6e3k mentioned but not cited (6)

  1. Structure of the IFNγ receptor complex guides design of biased agonists. Mendoza JL, Escalante NK, Jude KM, Sotolongo Bellon J, Su L, Horton TM, Tsutsumi N, Berardinelli SJ, Haltiwanger RS, Piehler J, Engleman EG, Garcia KC. Nature 567 56-60 (2019)
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Reviews citing this publication (15)

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  3. Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides. Sharma P, Marada VVVR, Cai Q, Kizerwetter M, He Y, Wolf SP, Schreiber K, Clausen H, Schreiber H, Kranz DM. Proc Natl Acad Sci U S A 117 15148-15159 (2020)
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  5. Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist. Glassman CR, Su L, Majri-Morrison SS, Winkelmann H, Mo F, Li P, Pérez-Cruz M, Ho PP, Koliesnik I, Nagy N, Hnizdilova T, Picton LK, Kovar M, Bollyky P, Steinman L, Meyer E, Piehler J, Leonard WJ, Garcia KC. Elife 10 e65777 (2021)
  6. LncRNA TINCR impairs the efficacy of immunotherapy against breast cancer by recruiting DNMT1 and downregulating MiR-199a-5p via the STAT1-TINCR-USP20-PD-L1 axis. Wang Q, Li G, Ma X, Liu L, Liu J, Yin Y, Li H, Chen Y, Zhang X, Zhang L, Sun L, Ai J, Xu S. Cell Death Dis 14 76 (2023)
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  26. Determination of a distinguished interferon gamma epitope recognized by monoclonal antibody relating to autoantibody associated immunodeficiency. Yasamut U, Wisitponchai T, Lee VS, Yamabhai M, Rangnoi K, Thongkum W, Chupradit K, Tayapiwatana C. Sci Rep 12 7608 (2022)
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