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Cysteine-reactive free ISG15 generates IL-1β-producing CD8α+ dendritic cells at the site of infection

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posted on 07.09.2020 by Anna Napolitano, Annemarthe G van der Veen, Monique Bunyan, Annabel Borg, David Frith, Steven Howell, Svend Kjaer, Antje Beling, Ambrosius P Snijders, Klaus-Peter Knobeloch, Eva-Maria Frickel
IFN-stimulated gene (ISG) 15 is a ubiquitin-like protein induced after type I IFN stimulation. There is a dearth of in vivo models to study free unconjugated ISG15 function. We found that free ISG15 enhances the production of IFN-γ and IL-1β during murine infection with Toxoplasma gondii In our model, ISG15 is induced in a type I IFN-dependent fashion and released into the serum. Increased ISG15 levels are dependent on an actively invading and replicating parasite. Two cysteine residues in the hinge domain are necessary determinants for ISG15 to induce increased cytokine levels during infection. Increased ISG15 is concurrent with an influx of IL-1β-producing CD8α+ dendritic cells to the site of infection. In this article, we present Toxoplasma infection as a novel in vivo murine model to study the immunomodulatory properties of free ISG15 and uniquely link it to IL-1β production by CD8α+ dendritic cells driven by two cysteines in the hinge region of the protein.

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