['To determine the antigenic determinants and specific molecular requirements for the generation of autoregulatory neuroantigen-specific CD8(+) T cells in models of multiple sclerosis (MS).', 'We have previously shown that MOG35-55-specific CD8(+) T cells suppress experimental autoimmune encephalomyelitis (EAE) in the C57BL/6 model. In this study, we utilized multiple models of EAE to assess the ability to generate autoregulatory CD8(+) T cells.', 'We demonstrate that alternative myelin peptides (PLP178-191) and other susceptible mouse strains (SJL) generated myelin-specific CD8(+) T cells, which were fully capable of suppressing disease. The disease-ameliorating function of these cells was dependent on the specific cognate myelin antigen. Generation of these autoregulatory CD8(+) T cells was not affected by thymic selection, but was dependent on the presence of both CD4(+) and CD8(+) T-cell epitopes in the immunizing encephalitogenic antigen.'] Do autoregulatory CD8 T cells depend on cognate antigen recognition and CD4/CD8 myelin determinants?