ISG15 modulates inflammatory profiles and ability to activate CD8 + T cells in bone marrow-derived dendritic cells

TL;DR

This study shows that ISG15 helps control inflammation and T cell activation in dendritic cells, which are important for immune responses.

Contribution

The study reveals a novel role for ISG15 in modulating dendritic cell inflammatory activity and CD8+ T cell responses.

Findings

Isg15−/− BMDCs showed reduced CD40 induction and lower secretion of IL-1β and IL-12.

Isg15−/− BMDCs induced less proliferation and Granzyme B expression in CD8+ T cells.

ISG15 regulates Caspase-1 activity, affecting IL-1β secretion in dendritic cells.

Abstract

The Interferon-Stimulated Gene 15 (ISG15) has a key role during viral infections, since it can modify and regulate the expression of proteins from the host and from viruses. Isg15−/− mice are more susceptible to infectious diseases. ISG15 is induced by type I Interferons (IFN-I) and apart from defense against pathogens, it can also play an important function in cancer or immune-mediated inflammatory diseases. Previous studies reported that ISG15 expression is increased in post-synaptic dendritic cells (DCs) upon interaction with CD4 + T cells. However, data regarding the role of ISG15 in DCs are scarce. The present study assesses the function of ISG15 in DCs activation, migration and ability to mediate T cell activation using bone marrow-derived DCs (BMDCs) and stimulation with lipopolysaccharide (LPS). Activation of DCs was not impaired but tended to be lower in Isg15-deficient mice, as observed by reduced CD40 induction in Isg15−/− BMDCs. Isg15−/− BMDCs induced less proliferation and Granzyme B expression in co-cultured CD8 + T cells. Interestingly, Isg15−/− BMDCs secreted reduced levels of the pro-inflammatory cytokines IL-1β and IL-12 upon LPS stimulation. Mechanistically, our data suggest that ISG15 regulates Caspase-1 activity in DCs leading to lower IL-1 β secretion. In conclusion, this study reveals an essential role for ISG15 modulating DCs inflammatory activity and raises new questions regarding the specific mechanisms of how this protein regulates innate immune responses.

The online version contains supplementary material available at 10.1007/s00018-025-05849-9.

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