We show here that the extent of T cell activation within the tissue is a critical parameter for the formation of astrocyte-destructive lesions in NMO-IgG seropositive rats, and we provide evidence for the presence of activated CD4+ T cells in CNS lesions of NMO patients, suggesting that these lesions have been initiated by pathogenic T cells recognizing antigens in the CNS. Here, CD4 is linked to neuromyelitis optica.