Structure of the IFN? receptor complex guides design of biased agonists.

ABSTRACT: The cytokine interferon-? (IFN?) 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 IFN? pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFN? receptor IFN?R1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFN?-IFN?R1-IFN?R2 signalling complex at 3.25 Å resolution. The structure reveals the mechanism underlying deficits in IFN? responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFN?R2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFN? variants to tune IFN? receptor signalling output. Unexpectedly, we found that several partial IFN? 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 IFN? for therapeutic applications.

SUBMITTER: Mendoza JL 

PROVIDER: S-EPMC6561087 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature