Two 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 programmed cell death (PCD) including specific Ag. We have demonstrated previously that Ag induces the death of encephalitogenic T cells in vitro and deletion in vivo, leading to amelioration of autoimmune encephalomyelitis. We have now examined whether activated, myelin basic protein (MBP)-specific human T cells may be eliminated by Ag-induced PCD. We demonstrate that activated MBP-specific T cell lines (TCL) undergo the classic nuclear morphologic changes and DNA fragmentation characteristic of apoptosis when given a TCR challenge. We found evidence that two mechanisms led to apoptosis: a propriocidal mechanism that was highly Ag-specific and dependent on the dose of exogenously added rIL-2, and a cytolytic mechanism in which MBP-specific TCL lysed B cell targets and engaged in considerable "fratricidal" cytolysis of other MBP-specific T cells. These two pathways leading to MBP-specific apoptotic death could be distinguished by their glucocorticoid sensitivity. Glucocorticoid treatment significantly blocked MBP-induced propriocidal apoptosis but had no effect on T cell cytolysis of B cell targets. Although it has been proposed that autoimmune disease could result from the failure of normal deletional mechanisms, this preliminary survey of MBP-reactive mature TCL from multiple sclerosis patients revealed that such cells are highly susceptible to TCR-induced PCD and comparable with TCL from normal subjects. Thus, therapeutic strategies based on Ag-induced PCD of T lymphocytes may be feasible in man.
Pelfrey
C M
CM
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Tranquill
L R
LR
Boehme
S A
SA
McFarland
H F
HF
Lenardo
M J
MJ
D017209:Apoptosis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008222:Lymphokines / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D001324:Autoantigens; D005938:Glucocorticoids; D008222:Lymphokines; D004676:Myelin Basic Protein