Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4(+) T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes(+) CD4(+) T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes(+) CD4(+) T cells.