It is probable that myelin-reactive T cells, including those specific for myelin basic protein (MBP) contribute to the pathogenesis of multiple sclerosis (MS). Although many studies have characterized the specificity, MHC restriction, and V gene use of MBP-specific T cells, there is little agreement as to whether there are differences between MS and controls, and how HLA-DR2, a risk factor for MS, might influence selection of MBP-specific T cells. We here discuss models in which MHC class II alleles could help shape the TCR repertoire, and then review more than 750 clones reported in the literature. The major finding from our analysis is that both TCRAV8 and BV5, but not BV6 were utilized more frequently in MS patients than non-MS patients in response to MBP, although no differences were found between DR2+ versus DR2- donors. These data indicate HLA-independent differences in the T cell repertoire between MS patients and controls that may be important for targeted TCR-based therapy. Moreover, we conclude that (1) HLA-DR alleles preferentially restrict MBP responses, although MS patients tend to use HLA-DQ and -DP alleles more often than control donors; (2) HLA-DR2 alleles are used to restrict only about half the MBP responses in MS patients, significantly less than in control patients; (3) the DRB1*1501 and DRB5*0101 subtypes within the Dw2 haplotype are used relatively equally to restrict MBP responses. In this context, we review the results of our previous clinical trials in progressive MS patients, demonstrating the ability of TCRBV5S2 peptides to induce clinically relevant regulatory responses that inhibit MBP-specific Th1 cells through a bystander suppression mechanism.