Differential outcome of tolerance induction in naive versus activated Theiler's virus epitope-specific CD8⁺ cytotoxic T cells

Tolerance induced by the intravenous injection of peptide-pulsed, ethylene carbodiimide (ECDI)-fixed splenic antigen-presenting cells (Ag-SP) is a safe and effective method of inducing specific unresponsiveness in CD4⁺ T cells for the prevention and treatment of a variety of autoimmune diseases. We determined whether Ag-SP tolerance could also be used to tolerize CD8 ⁺ T cells. We show in the Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease model of multiple sclerosis that CD8 ⁺ T cells specific for both dominant and subdominant epitopes can be rendered tolerant. Interestingly, although virus clearance was delayed, lack of the virus-specific cytotoxic T-lymphocyte response did not result in the conversion of normally TMEV-resistant C57BL/6 mice to a susceptible phenotype. Importantly, we found that Ag-SP tolerance may not be a practical treatment for human diseases in which CD8⁺ T cells play a major role in pathogenesis, as tolerance induction in mice previously infected with TMEV led to a severe, often fatal reaction.