CD4(+) T cells specific for immunologic non-self determinants on self-IgG, idiotopes (Id), can be raised from cerebrospinal fluid (CSF) and blood of patients with multiple sclerosis (MS). To test if Id-specific CD4(+) T cells have the potential to destroy oligodendrocytes (ODCs), we analyzed their ability to induce apoptosis of human ODC cell lines. Id-specific CD4(+) T cells stimulated with either Id-bearing B cells, Id-peptide presented by other antigen presenting cells, or by anti-CD3/anti-CD28 in the absence of accessory cells induced DNA fragmentation and killed ODCs. Killing required contact between the ODCs and the T cells, it did not depend on the cytokine profile of the T cells, it was independent of other cell types, and was inhibited by a general caspase inhibitor and an anti-Fas antibody. Activated CD4(+) T cells specific for glutamic acid decarboxylase 65 also induced apoptosis, showing that killing does not depend on cognate interaction between T cells and target cells but rather on the activation status of the T cells.