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Article Dans Une Revue Nature Immunology Année : 2023

IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Josephine Kemna
  • Fonction : Auteur
Evelyne Gout
Leon Daniau
  • Fonction : Auteur
Jessica Lao
  • Fonction : Auteur
Kristoffer Weißert
Sandra Ammann
Ralf Kühn
Matthias Richter
Christine Molenda
Anje Sporbert
  • Fonction : Auteur
Dario Zocholl
Robert Klopfleisch
  • Fonction : Auteur
Hugues Lortat-Jacob
Peter Aichele
Thomas Kammertoens
  • Fonction : Auteur
Thomas Blankenstein

Résumé

Abstract Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ ΔKRKR ) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ ΔKRKR 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 IFNγ ΔKRKR mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ ΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation.

Dates et versions

hal-03974972 , version 1 (06-02-2023)

Identifiants

Citer

Josephine Kemna, Evelyne Gout, Leon Daniau, Jessica Lao, Kristoffer Weißert, et al.. IFNγ binding to extracellular matrix prevents fatal systemic toxicity. Nature Immunology, 2023, ⟨10.1038/s41590-023-01420-5⟩. ⟨hal-03974972⟩
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