IL-17-producing CD8+ T (Tcl7) cells are detectible in multiple sclerosis (MS) lesions; however, their contri-bution to the disease is unknown. To identify functions of Tel 7 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tcl7 and Thl7 cells and were resistant to EAE. After adoptive transfer of WT CD8+ T cells and subsequent immunization for EAE induction in these mice, the CD8+ T cells developed a Tcl7 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4+ T cells alone did not evoke EAE, but when trans-ferred together with CD8+ T cells, IL-17-producing CD4+ (Thl7) T cells accumulated in the CNS and mice developed severe disease. Thl7 accumulation and development of EAE required IL-17A production by CD8+ T cells, suggesting that Tcl7 cells are required to promote CD4+ T cell-mediated induction of EAE. Accord-ingly, patients with early-stage MS harbored a greater number of Tcl7 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tcl7 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Thl7 cell pathogenicity. [ABSTRACT FROM AUTHOR]