This study has examined the cellular response to myelin basic protein (MBP) in a multiplex family with multiple sclerosis (MS). A total of 81 MBP-specific T cell lines (TCLs) were derived from three affected siblings and four healthy siblings. No difference was observed in estimated precursor frequencies of MBP-specific TCLs or peptide specificity of TCLs when comparing affected and unaffected siblings. MBP-specific TCLs from affected siblings, however, were restricted to the DRw15/DQw6 allele more frequently than those from unaffected siblings (P < 0.02). These data suggest that restriction of autoantigen-specific T cells may be the functional basis for disease susceptibility related to HLA class II inheritance.