2 MECHANISMS OF ANTIGEN-SPECIFIC APOPTOSIS OF MYELIN BASIC-PROTEIN (MBP)-SPECIFIC T-LYMPHOCYTES DERIVED FROM MULTIPLE-SCLEROSIS PATIENTS AND NORMAL INDIVIDUALS

Several stimuli induce mature T cells to undergo apoptosis or programm ed cell death (PCD) including specific Ag. We have demonstrated previo usly that Ag induces the death of encephalitogenic T cells in vitro an d deletion in vivo, leading to amelioration of autoimmune encephalomye litis. We have now examined whether activated, myelin basic protein (M BP)-specific human T cells may be eliminated by Ag-induced PCD. We dem onstrate that activated MBP-specific T cell lines (TCL) undergo the cl assic nuclear morphologic changes and DNA fragmentation characteristic of apoptosis when given a TCR challenge. We found evidence that two m echanisms led to apoptosis: a propriocidal mechanism that was highly A g-specific and dependent on the dose of exogenously added rlL-2, and a cytolytic mechanism in which MBP-specific TCL lysed B cell targets an d engaged in considerable ''fratricidal'' cytolysis of other MBP-speci fic T cells. These two pathways leading to MBP-specific apoptotic deat h could be distinguished by their glucocorticoid sensitivity. Glucocor ticoid treatment significantly blocked MBP-induced propriocidal apopto sis but had no effect on T cell cytolysis of B cell targets. Although it has been proposed that autoimmune disease could result from the fai lure of normal deletional mechanisms, this preliminary survey of MBP-r eactive mature TCL from multiple sclerosis patients revealed that such cells are highly susceptible to TCR-induced PCD and comparable with T CL from normal subjects. Thus, therapeutic strategies based on Ag-indu ced PCD of T lymphocytes may be feasible in man.