| First Author | Kemna J | Year | 2023 |
| Journal | Nat Immunol | Volume | 24 |
| Issue | 3 | Pages | 414-422 |
| PubMed ID | 36732425 | Mgi Jnum | J:335280 |
| Mgi Id | MGI:7468838 | Doi | 10.1038/s41590-023-01420-5 |
| Citation | Kemna J, et al. (2023) IFNgamma binding to extracellular matrix prevents fatal systemic toxicity. Nat Immunol 24(3):414-422 |
| abstractText | Interferon-gamma (IFNgamma) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNgamma binds to its receptor (IFNgammaR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNgamma is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNgamma lacking the EBD (IFNgamma(DeltaKRKR)) does not bind to ECM but still binds to the IFNgammaR and retains bioactivity. Overexpression of IFNgamma(DeltaKRKR) 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 IFNgamma(DeltaKRKR) mice lacking the EBD by using CRISPR-Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNgamma(DeltaKRKR) levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNgamma is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation. |
