In a previous study, we showed that the Ly6G(-)CD11b(+) blood monocytes residing in naïve mice are intrinsically immunosuppressive and that loss of this suppressive function may contribute to the development of autoimmunity in experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis. Here we report that mice treated with a modified superantigen coupled to myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55)) peptide (DM-MOG(35-55)) suppressed the development of EAE. The treatment was associated with impaired MOG(35-55)-specific T cell proliferation and a decrease in IL-17 and IFNγ production in the draining lymph nodes. Analysis of circulating blood immune cells showed that the suppressor function of Ly6G(-)CD11b(+) blood monocytes was reduced in EAE mice, but was restored in mice treated with DM-MOG(35-55). Importantly, adoptive transfer of blood CD11b(+)Ly6G(-) cells isolated from DM-MOG(35-55)-treated mice protected recipient mice from developing EAE. Together, these results show that DM coupled to the auto-antigen MOG(35-55): 1) suppresses EAE via antigen-specific suppression of T cell responses, and 2) re-establishes suppressor function of Ly6G(-)CD11b(+) blood monocytes. Auto-antigens coupled to DM could therefore represent a new therapeutic approach for controlling inappropriate inflammation in autoimmune diseases such as multiple sclerosis by inducing antigen-specific T cell suppression.