IFNγ binding to extracellular matrix prevents fatal systemic toxicity

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

doi:10.1038/s41590-023-01420-5

IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Nat Immunol. 2023 Mar;24(3):414-422. doi: 10.1038/s41590-023-01420-5. Epub 2023 Feb 2.

Authors

Josephine Kemna¹, Evelyne Gout², Leon Daniau^{3

4}, Jessica Lao^{3

4}, Kristoffer Weißert^{3

4

5}, Sandra Ammann^{3

5}, Ralf Kühn⁶, Matthias Richter⁷, Christine Molenda⁷, Anje Sporbert⁷, Dario Zocholl⁸, Robert Klopfleisch⁹, Anja Schütz¹⁰, Hugues Lortat-Jacob², Peter Aichele^{3

5}, Thomas Kammertoens^{1

11}, Thomas Blankenstein¹²

Affiliations

¹ Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Molecular Immunology and Gene Therapy, Berlin, Germany.
² Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Grenoble, France.
³ Institute for Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁴ Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
⁵ Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁶ Transgenic Core Facility, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁷ Advanced Light Microscopy Core Facility, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁸ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Berlin, Germany.
⁹ Department of Veterinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
¹⁰ Protein Production & Characterization Core Facility, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
¹¹ Institute of Immunology, Charité Unversitätsmedizin, Campus Buch, Berlin, Germany.
¹² Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Molecular Immunology and Gene Therapy, Berlin, Germany. tblanke@mdc-berlin.de.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines* / metabolism
Extracellular Matrix / metabolism
Interferon-gamma / metabolism
Mice
Neoplasms*
Signal Transduction

Substances

Cytokines
Interferon-gamma