Natural killer (NK) cells can affect the outcome of adaptive immune responses. NK cells, but not NK1.1+T cells, were found to participate in the development of myasthenia gravis (a T cell-dependent, B cell- and antibody-mediated autoimmune disease) in C57BL/6 mice. The requirement for NK cells was reflected by the lack of a type I helper T cell response and antibodies to the acetylcholine receptor in both NK1.1+ cell-depleted and NK cell-deficient IL-18-/- mice. These findings establish a previously unrecognized link between NK cells and autoreactive T and B cells.

Autoantigen administration via nasal mucosal tissue can induce systemic tolerance more effectively than oral administration in a number of experimental autoimmune diseases, including Ab-mediated experimental autoimmune myasthenia gravis, a murine model of myasthenia gravis. The mechanisms underlying nasal tolerance induction are not clear. In this study, we show that nasal administration 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 were associated with decreased AChR-specific lymphocyte proliferation and decreased levels of anti-AChR Abs of the IgG2a and IgG2b isotypes in serum. The clinical and immunological changes in the AChR-pretreated C57BL/6 wild-type (wt) mice were comparable with those observed in AChR-pretreated CD8−/− mice, indicating that CD8+ T cells were not required for the generation of nasal tolerance. AChR-pretreated wt and CD8−/− mice showed augmented TGF-β and reduced IFN-γ responses, whereas levels of IL-4 were unaltered. Splenocytes from AChR-pretreated wt and CD8−/− mice, but not from CD4−/− mice, suppressed AChR-specific lymphocyte proliferation. This suppression could be blocked by Abs against TGF-β. Thus, our results demonstrate that the suppression induced in the present model is independent of CD8+ T cells and suggest the involvement of Ag-specific CD4+ Th3 cells producing TGF-β.