We have generated TCR transgenic mice (T/R+) specific for myelin basic protein (MBP) and crossed them to RAG-l-deficient mice to obtain mice (T/R-) that have T cells expressing the transgenic TCR but no other lymphocytes. Both T/R+ and T/R-mice carry, in the lymph nodes and spleen, large numbers of the potentially encephalitogenic CD4+ anti-MBP T cells. These ceils respond to MBP in vitro but show no signs of activation in vivo. Nevertheless,-14% of H-2” T/R+ and 100% of H-2” T/R-mice developed spontaneous experimental autoimmune encephalomyelitis(EAE) within 12 months. These data indicate that EAE can be mediated by CD4+ anti-MBP T cells in the absence of any other lymphocytes and that nontransgenic lymphocytes that are present in T/R+ but absent in T/R-mice have a protective effect. The data also suggest that spontaneous EAE may be triggered by an in situ activation of CD4+ anti-MBP cells in the nervous system.