Trimolecular interactions between the T cell antigen receptor and MHC/peptide complexes, together with costimulatory molecules and cytokines, control the initial activation of naïve T cells and determine whether the helper precursor cell differentiates into either T helper (TH)1 or TH2 effector cells. We now present evidence that regulatory CD8⁺ T cells provide another level of control of TH phenotype during further evolution of immune responses. These regulatory CD8⁺ T cells are induced by antigen-triggered CD4⁺ TH1 cells during T cell vaccination and, in vitro, distinguish mature TH1 from TH2 cells in a T cell antigen receptor Vβ-specific and Qa-1-restricted manner. In vivo, protection from experimental autoimmune encephalomyelitis (EAE) induced by T cell vaccination depends on CD8⁺ T cells, and myelin basic protein-reactive TH1 Vβ8⁺ clones, but not TH2 Vβ8⁺ clones, used as vaccine T cells, protect animals from subsequent induction of EAE. Moreover, in vivo depletion of CD8⁺ T cells during the first episode of EAE results in skewing of the TH phenotype toward TH1 upon secondary myelin basic protein stimulation. These data provide evidence that CD8⁺ T cells control autoimmune responses, in part, by regulating the TH phenotype of self-reactive CD4⁺ T cells.