IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Interferon-gamma (IFN gamma) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFN gamma binds to its receptor (IFN gamma R) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFN gamma is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFN gamma lacking the EBD (IFN gamma(Delta KRKR)) does not bind to ECM but still binds to the IFN gamma R and retains bioactivity. Overexpression of IFN gamma(Delta KRKR) in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFN gamma(Delta KRKR) mice lacking the EBD by using CRISPR-Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFN gamma(Delta KRKR) levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFN gamma is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation. Here, the authors show that IFN gamma binding to heparan sulfate is a mechanism to restrain IFN gamma at the site of production, thereby preventing high systemic levels of this cytokine and associated immunopathology.

Automated summary

The study demonstrates that the extracellular matrix (ECM)-binding domain (EBD) of interferon-gamma (IFN gamma) is crucial for preventing high systemic levels of this cytokine and related immunopathology. Lack of EBD in IFN gamma significantly reduces ECM binding but retains the binding to IFN gamma receptor and bioactivity. Overexpression of EBD-deficient IFN gamma results in increased systemic levels, sickness behavior, weight loss, and toxicity.