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Publication Abstract from PubMed

The cytokine interferon-gamma (IFNgamma) 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 IFNgamma pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNgamma receptor IFNgammaR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNgamma-IFNgammaR1-IFNgammaR2 signalling complex at 3.25 A resolution. The structure reveals the mechanism underlying deficits in IFNgamma responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNgammaR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNgamma variants to tune IFNgamma receptor signalling output. Unexpectedly, we found that several partial IFNgamma 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 IFNgamma for therapeutic applications.

Structure of the IFNgamma 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. 2019 Mar;567(7746):56-60. doi: 10.1038/s41586-019-0988-7. Epub 2019 Feb, 27. PMID:30814731^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.