RT Journal Article SR Electronic T1 Free ISG15 as a dimer generates IL-1β-producing CD8α+ dendritic cells at the site of infection JF bioRxiv FD Cold Spring Harbor Laboratory SP 111658 DO 10.1101/111658 A1 Anna Napolitano A1 Annemarthe G. van der Veen A1 Monique Bunyan A1 Annabel Borg A1 Svend Kjaer A1 Antje Beling A1 Klaus-Peter Knobeloch A1 Eva Frickel YR 2017 UL http://biorxiv.org/content/early/2017/02/27/111658.abstract AB ISG15 is strongly induced after type I IFN stimulation producing a protein comprised of two ubiquitin-like domains. Intracellularly, ISG15 can be covalently linked and modify the function of target proteins (ISGylation). In addition, free unconjugated ISG15 can be released from cells. We found that ISG15 is released in the serum of Toxoplasma gondii infected mice early after infection in a type-I IFN independent manner. Once in the extracellular space, free ISG15 forms dimers and enhances the release of key cytokines involved in the immune response to the parasite: IL-12, IFN-γ, and IL-1β. Its action is dependent on an actively invading and replicating live parasite. ISG15 induces an increase of IL-1β later during infection by leading to increased IL-1β producing CD8α+ dendritic cells at the site of infection. Here, we define for the first time the molecular determinants of active free ISG15 and link ISG15 to IL-1β production by CD8α+ dendritic cells. Thus we define ISG15 as a novel secreted modulator of the cytokine response during Toxoplasma infection.