Although autoreactive T cells recognizing self myelin Ags are present in most individuals, autoimmune disease of the central nervous system is a relatively rare medical condition. Development of autoimmune disease may require not only the presence of autoreactive T cells but also that autoreactive T cells become activated. Activation of T cells may require a minimum of two signals: an Ag-specific signal delivered by MHC-peptide complex and a second signal delivered by costimulatory molecules or cytokines. Although in vitro studies have suggested that cytokines, especially proinflammatory cytokines such as IL-1, IL-6, and TNF are involved in T cell activation, their precise roles in vivo are not clear. To determine the roles of proinflammatory cytokines in T cell activation in vivo and in the development of autoimmune disease, we have studied experimental autoimmune encephalomyelitis (EAE) in mice deficient in IL-6. We found that IL-6-deficient mice were completely resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG), whereas IL-6-competent control mice developed EAE characterized by focal inflammation and demyelination in the central nervous system and deficiency in neurologic functions. Furthermore, we established that the resistance to EAE in IL-6-deficient mice was associated with a deficiency of MOG-specific T cells to differentiate into either Th1 or Th2 type effector cells in vivo. These results strongly suggest that IL-6 plays a crucial role in the activation and differentiation of autoreactive T cells in vivo and that blocking IL-6 function can be an effective means to prevent EAE.