Impaired apoptotic deletion of myelin basic protein-reactive T cells in patients with multiple sclerosis

T cell responses to myelin basic protein (MBP) may play an important role i n the pathogenesis of multiple sclerosis (MS). If MBP-reactive T cells are involved in the disease processes and undergo clonal activation and expansi on, their precursor frequency would be increased in patients with MS. The f requency of MBP-reactive T cells is also influenced by regulatory mechanism s in vivo, including apoptotic deletion. In this study, we examined changes in the frequency of MBP-reactive T cells in patients with MS as a function of the apoptotic deletional mechanism in vivo, using a cell culture-based assay. A significantly increased frequency of MBP-reactive T cells was foun d in patients with MS relative: to healthy individuals only when Fas-ligand antibody was used to block apoptosis. This result indicates that a signifi cant proportion of MBP-reactive T cells are sensitive to apoptosis and are not deleted in vivo in patients with MS, as opposed to healthy individuals, thus suggesting a functional deficit in apoptotic deletional mechanism. Su rviving Fas-sensitive MBP-reactive T cell lines represent distinct subpopul ations preferentially recognizing the 111-139 region of MBP and exhibiting a Th2 cytokine profile. The findings are relevant to our understanding of r egulation of MBP-reactive T cells in vivo in MS.