Vaccination of mice with activated autoantigen-reactive CD4 ؉ T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8 ؉ regulatory T cells that are specific for pathogenic CD4 ؉ T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8 ؉ T cells emerge that preferentially lyse and regulate activated autologous CD4؉ T cells in a T cell receptor (TCR) V␤-specific manner. This TCR V␤-specific regulation is not observed in ␤ 2 -microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar V␤8-specific Qa-1-restricted CD8 ؉ T cells are also induced by TCV with activated CD4 ؉ V␤8 ؉ T cells. These CD8 ؉ T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR V␤8. Further, CD8؉ T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4 ؉ V␤8 ؉ T cell clone specifically recognize other CD4 ؉ T cells and T cell tumors that express V␤8 and the syngeneic Qa-1 a but not the allogeneic Qa-1 b molecule. Thus, V␤-specific Qa-1-restricted CD8 ؉