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Geometric Tuning of Cytokine Receptor Association Modulates Synthetic Agonist Signaling
Marc Expòsit1,2,3, Mohamad Abedi1,2, Aditya Krishnakumar1,2
1Department of Biochemistry, University of Washington, Seattle, WA, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
Researchers developed a novel protein design platform to control cytokine receptor geometry. This allows precise tuning of immune cell signaling pathways and functional outcomes, enabling programmable immune modulation.
Area of Science:
- Immunology
- Protein Engineering
- Systems Biology
Background:
- Cytokines mediate cellular communication by assembling receptor subunits.
- The precise role of receptor geometry in cytokine signaling is poorly understood due to fixed natural ligand assemblies.
- Understanding this geometry is crucial for deciphering and controlling immune responses.
Purpose of the Study:
- To develop a de novo protein design platform for precise control over cytokine receptor geometry.
- To investigate how varying receptor geometry influences downstream signaling pathways (pSTAT) and cellular functions.
- To explore the potential for programmable immune modulation through geometric control of cytokine signaling.
Main Methods:
- Engineered a de novo protein design platform to rigidly scaffold receptor-binding domains into defined spatial arrangements.
- Applied the platform to various cytokine receptor systems including IL-7, type I/III interferons, IL-10, gp130, and beta common.
- Analyzed the impact of altered receptor geometry on pSTAT pathway activation and specific cellular functions like antigen presentation, checkpoint induction, and cytokine secretion.
Main Results:
- Demonstrated that varying receptor geometry can bias pSTAT pathway usage and tune functional outcomes.
- Successfully decoupled specific signaling outputs, such as separating pSTAT1 from pSTAT5 for IL-7.
- Achieved selective modulation of functions, like separating antigen presentation (MHC-I) from checkpoint induction (PD-L1) in type I interferons, and fine-tuning IL-10 activity.
- Created minimal agonists for IL-6 and IL-3, and enhanced synthetic receptor pairings.
Conclusions:
- Receptor geometry is a critical determinant of cytokine activity and signaling specificity.
- The developed protein design platform offers a powerful tool for dissecting cytokine mechanisms.
- This platform enables the creation of novel immunomodulatory agents with programmable functions.
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