Autoantigen administration via nasal mucosal tissue can induce systemic tolerance more effectively than oral administration in anumber of experimental autoimmune diseases, including Ab-mediated experimental autoimmune myasthenia gravis, a murinemodel of myasthenia gravis. The mechanisms underlying nasal tolerance induction are not clear. In this study, we show that nasaladministration of acetylcholine receptor (AChR) in C57BL/6 mice, before immunizations with AChR in adjuvant, results in delayed onset and reduced muscle weakness compared with control mice. The delayed onset and reduced muscle weakness wereassociated with decreased AChR-specific lymphocyte proliferation and decreased levels of anti-AChR Abs of the IgG2a and IgG2bisotypes in serum. The clinical and immunologicalchanges in the AChR-pretreated C57BL/6 wild-type (wt) mice were comparable with those observed in AChR-pretreated CD82/2 mice, indicating that CD81 T cells were not requiredfor the generation of nasaltolerance. AChR-pretreated wt and CD82/2 mice showed augmented TGF-b and reduced IFN-g responses, whereas levels of IL-4were unaltered. Splenocytes from AChR-pretreated wt and CD82/2 mice, but not from CD42/2 mice, suppressed AChR-specificlymphocyte proliferation. This suppression could be blocked by Abs against TGF-b. Thus, our results demonstrate that the suppression induced in the present model is independent of CD81 T cells and suggest the involvementof Ag-specific CD41 Th3cells producing TGF-b.