Abstract Experimental autoimmune encephalitis (EAE) is an induced autoimmune disorder in rodent animals with the development of autoimmune T cells attacking axonal myelin protein causing demyelination. This model has been widely used to develop preventive or therapeutic approaches for human multiple sclerosis (MS). In current study, we report that infusion of SMCC-conjugated MOG35-55 coupled autologous spleen cells (either live, or ultraviolet B-irradiated apoptotic) significantly prevents and reverses EAE in mice. Further studies show that the protected animals resist EAE re-induction by MOG35-55 antigen challenge. Moreover, adoptive transfer of CD4+ T cells from the protected mice to naïve syngeneic mice renders the recipients resistant to EAE induction, suggesting that MOG35-55-specific regulatory CD4+ T cells may be induced. Unexpectedly, CD4+T cell proliferation is similar upon ex vivo stimulation by MOG35-55 amongst all groups. However, further analysis of those proliferating CD4+ T cells shows remarkable difference in Foxp3+ cells (70% in MOG-SP groups versus 10-25% in control groups, p<0.05), and in IL-17+ cells (2-3% in MOG-SP groups versus 6-9% in control groups,p<0.05). These findings indicate that MOG35-55 coupled spleen cell treatment induces MOG35-55 specific regulatory T cells, and suppresses EAE pathogenic Th17 cells. Our study provides a novel approach for antigen-based immunotherapy for EAE, which has a great potential for developing immunotherapies for MS .