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Characterization of the Antigen Specificity and TCR Repertoire, and TCR-Based DNA Vaccine Therapy in Myelin Basic Protein-Induced Autoimmune Encephalomyelitis in DA Rats¹

Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

Like Lewis rats, DA rats are an experimental autoimmune encephalomyelitis (EAE)-susceptible strain and develop severe EAE upon immunization with myelin basic protein (MBP). However, there are several differences between the two strains. In the present study we induced acute EAE in DA rats by immunization with MBP and MBP peptides and examined the Ag specificity and TCR repertoire of encephalitogenic T cells. It was found that although immunization with MBP and a peptide corresponding to its 62–75 sequence (MBP_62–75) induced clinical EAE, the responses of lymph node T cells isolated from MBP-immunized rats to MBP_62–75 was marginal, indicating that this peptide contains major encephalitogenic, but not immunodominant, epitopes. The TCR analysis by CDR3 spectratyping of spinal cord T cells revealed that V10 and V15 spectratype expansion was always found in MBP_62–75-immunized symptomatic rats. On the basis of these findings, we examined the encephalitogenicity of V10- and V15-positive T cells. First, the adoptive transfer experiments revealed that V10-positive T line cells derived from MBP_62–75-immunized rats induced clinical EAE in recipients. Second, administration of DNA vaccines encoding V10 and V15, alone or in combination, ameliorated MBP_62–75-induced EAE. Collectively, it was strongly suggested that V10- and V15-positive T cells are encephalitogenic. Analyses of the Ag specificity and T cell repertoire of pathogenic T cells performed in this study provide useful information for designing specific immunotherapies against autoimmune diseases.

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