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Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease¹, which may be initiated by a virus infection². Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4⁺ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononu-clear inflammatory response mediated by virus-specific CD4⁺ T cells targeting virus, which chronically persists in the CNS (ref. 4–6). We show that beginning 3–4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139–151) did not arise because of …