Synthetic peptides corresponding to germline TCR V beta 8.2 sequences overexpressed by Lewis rat encephalitogenic T cells are effective in the prevention and treatment of autoimmune encephalomyelitis (EAE). In evaluating optimal conditions for identifying disease-relevant target V beta genes, we found that the biased expression of V beta 8.2 was most pronounced in the CNS among activated, IL-2 responsive T cells, but was weakly reflected in the cerebrospinal fluid. Evaluation of basic protein reactive T cells from patients with multiple sclerosis revealed biased expression of V beta 5.2 and to a lesser degree, V beta 6.1. Treatment of 11 MS patients with synthetic TCR V beta 5.2 and V beta 6.1 CDR2 peptides boosted the frequency of anti-TCR reactive T cells in a majority of patients, without compromising recall immunity or causing side effects. TCR peptides may be useful in the treatment of human autoimmune diseases, providing that disease-relevant V genes can be identified.