Stimulation of Ag‐specific inducible Treg can enhance resolution of autoimmune disease. Conventional methods to induce Treg often require induction of autoimmune disease or subjection to infection. Reovirus adhesin, protein σ1 (pσ1), can successfully facilitate tolerance when fused to a tolerogen. We tested whether myelin oligodendrocyte glycoprotein (MOG) fused to pσ1 (MOG‐pσ1) can stimulate Ag‐specific Treg. We show that C57BL/6 mice treated nasally with MOG‐pσ1 fail to induce MOG‐specific Abs and delayed‐type hypersensitivity (DTH) responses and resist EAE. Such resistance was attributed to stimulation of Foxp3⁺ Treg, as well as Th2 cells. MOG‐pσ1's protective capacity was abrogated in IL‐10^−/− mice, but restored when adoptively transferred with MOG‐pσ1‐induced Treg. As a therapeutic, MOG‐pσ1 diminished EAE within 24 h of nasal application, unlike recombinant MOG (rMOG), pσ1, or pσ1+rMOG, implicating the importance of Ag specificity by pσ1‐based therapeutics. MOG‐pσ1‐treated mice showed elevated IL‐4, IL‐10, and IL‐28 production by CD4⁺ T cells, unlike rMOG treated or control mice that produced elevated IFN‐γ or IL‐17, respectively. These data show the feasibility of using pσ1 as a tolerogen platform for Ag‐specific tolerance induction and highlight its potential use as an immunotherapeutic for autoimmunity.