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

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.