Experimental autoimmune encephalomyelitis (EAE) is the principal animal model for multiple sclerosis (MS). Here we demonstrate that the induction of EAE generates successive waves of clonally expanded CD4, CD8, and γδ T cells in the blood and central nervous system. In addition, we also demonstrate major expansions of CD8 T cells in the blood and cerebrospinal fluid of patients with MS. In EAE, we find that most expanded CD4 T cells are specific for myelin peptide MOG35-55. In contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8 T cells inhibit disease by suppressing the proliferation of MOG-specific CD4 T cells. Overall, our results suggest that the induction of autoreactive CD4 T cells triggers an opposing mobilization of regulatory CD8 T cells.