T cell receptor (TCR) vaccination in rats prevents the development of experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis. The mechanism of this potential immunotherapy was examined by vaccinating mice with an immunogenic peptide fragment of the variable region of the TCR V_β8.2 gene. Another immunogen that usually induces an immune response mediated by V_β8.2⁺ T cells was subsequently inhibited because specific clonal unresponsiveness (anergy) had been induced. Depletion of CD8⁺ cells before TCR peptide vaccination blocked such inhibition. Thus, the clonal anergy was dependent on CD8⁺ T cells, and such immunoregulatory T cells may participate in the normal course of EAE.