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) Vβ-specific manner. This TCR Vβ-specific regulation is not observed in β₂-microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar Vβ8-specific Qa-1-restricted CD8⁺ T cells are also induced by TCV with activated CD4⁺ Vβ8⁺ T cells. These CD8⁺ T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR Vβ8. Further, CD8⁺ T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4⁺Vβ8⁺ T cell clone specifically recognize other CD4⁺ T cells and T cell tumors that express Vβ8 and the syngeneic Qa-1^a but not the allogeneic Qa-1^b molecule. Thus, Vβ-specific Qa-1-restricted CD8⁺ T cells are induced by activated CD4⁺ T cells. We suggest that these CD8⁺ T cells may function to specifically regulate activated CD4⁺ T cells during immune responses.