Abstract

Cumulative evidence has established that Interferon (IFN)-? has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-? are not well understood. In this study, we found that IFN-? exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models. The frequency of regulatory T (Treg) cells in spinal cords from chronic EAE mice treated with IFN-? was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-?, indicating that the therapeutic effect of IFN-? depends on the presence of Treg cells. However, IFN-? did not trigger direct in vitro differentiation of Treg cells. In vivo administration of blocking antibodies against either interleukin (IL)-10, transforming growth factor (TGF)-? or program death (PD)-1, revealed that the protective effects of IFN-? in EAE were also dependent on TGF-? and PD-1, but not on IL-10, suggesting that IFN-? might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-? treatment increased the frequency of a subset of splenic CD11b+ myeloid cells expressing TGF-?-Latency Associated Peptide (LAP) and program death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)-1-dependent manner. Furthermore, splenic CD11b+ cells from EAE mice preconditioned in vitro with IFN-? and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of naïve CD4+ T cells mediated by secretion of TGF-?. Remarkably, adoptive transfer of splenic CD11b+ cells from IFN-?-treated EAE mice into untreated recipient mice ameliorated clinical symptoms of EAE and limited central nervous system infiltration of mononuclear cells and effector helper T cells. These results reveal a novel cellular and molecular mechanism whereby IFN-? promotes beneficial effects in EAE by endowing splenic CD11b+ myeloid cells with tolerogenic and therapeutic activities. © The Author(s) 2024.