Abstract

Cumulative evidence has established that Interferon (IFN)-gamma 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-gamma are not well understood. In this study, we found that IFN-gamma 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-gamma was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-gamma, indicating that the therapeutic effect of IFN-gamma depends on the presence of Treg cells. However, IFN-gamma 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)-beta or program death (PD)-1, revealed that the protective effects of IFN-gamma in EAE were also dependent on TGF-beta and PD-1, but not on IL-10, suggesting that IFN-gamma might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-gamma treatment increased the frequency of a subset of splenic CD11b(+) myeloid cells expressing TGF-beta-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-gamma and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of na & iuml;ve CD4(+) T cells mediated by secretion of TGF-beta. Remarkably, adoptive transfer of splenic CD11b(+) cells from IFN-gamma-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-gamma promotes beneficial effects in EAE by endowing splenic CD11b+ myeloid cells with tolerogenic and therapeutic activities.