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. 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.

“Designer cytokines” targeting the tumor vasculature—think global and act local

“…The second strategy to reduce unwanted side effects is based on changing the molecular interactions between TNF or IFNγ and their receptors. A prime example of such a strategy is the study by Mendoza et al () in which, based on the crystal structure of the IFNγ signaling complex, specific signaling agonists were designed by changing contact residues between the ligand and receptor chains, resulting in a molecule with reduced side effects for immunotherapy.…”

Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines

“…Moreover, cross-reactivity of the cytokine-binding homology region of gp130 for different IL-6 family cytokines has been shown by structural research . Indeed, such trials have begun even in cytokine receptor fields (Mendoza et al, 2019;Silva et al, 2019). Thus, structural studies suggest that high-resolution structural analysis of the receptor complex will open the way to developing small peptides or compounds with higher specificity and efficacy against autoimmune diseases.…”

A structural “star” in interferon gamma signaling

“…Mendoza and colleagues from the Garcia lab publish elegant work that describes the first crystal structure of the entire hexameric IFN‐γ signaling complex at 3.25 Å resolution . γ‐Interferon (IFN‐γ) is a critical cytokine for regulating immune response to pathogens and cancer cells.…”

“…In a recent edition of Nature , Mendoza and colleagues from the Garcia lab publish elegant work that describes the crystal structure of the hexameric IFN‐γ signaling complex (IFNγ ligand:IFNGR1:IFNGR2 at 2:2:2) at 3.25 Å resolution . Aided by affinity‐enhancement of IFNGR1 to stabilize the low‐affinity binding of IFNGR2 to the complex, the structure gives the cytokine field a look at the ternary type II IFN signaling complex for the first time, albeit with an IFNGR1 variant that contained six mutations.…”

“…Mendoza et al . used the structure to investigate the IFNGR2 mutation T168N that is associated with the lack of IFN‐γ responsiveness resulting in a predisposition to mycobacterial infection . The asparagine in the IFNGR2T168N mutant sits in the interface of IFNGR2 with the IFNg/IFNGR1 complex.…”