SUPERANTIGEN-DRIVEN, CD8(-CELL-MEDIATED DOWN-REGULATION - CD95 (FAS)-DEPENDENT DOWN-REGULATION OF HUMAN IG RESPONSES DESPITE CD95-INDEPENDENT KILLING OF ACTIVATED B-CELLS() T)

Staphylococcal superantigens, including staphylococcal enterotoxin B ( SEB), promote vigorous T cell-dependent Ig responses at low dose (0.01 ng/ml), In contrast, more mitogenic high dose SEE (100 ng/ml) profoun dly inhibits the Ig responses. To assess the contribution of CD8(+) T cells to this inhibition, high dose SEE-dependent killing of activated B cells and down-regulation of Ig responses were determined, Rapid ki lling (4 h) of activated B cells was effected by high dose SEE-activat ed CD8(+) T cells (CD8), but not by high-dose SEE-activated CD4(+) T cells (CD4), and required the presence of high dose SEE during the cy totoxicity assay. This killing was abrogated by chelation of extracell ular calcium or by treatment with concanamycin ii. but was only modest ly affected by treatment with brefeldin A, suggesting a perforin-based pathway of killing. Despite their widely disparate abilities to rapid ly kill activated B cells, CD8 and CD4* demonstrated similar quantita tive abilities to effect high dose SEB-dependent down-regulation of Ig responses. Antagonist anti-CD95 mAb substantially reversed high dose SEE-dependent downregulation effected by CD8 but had no appreciable e ffects on high dose SEE-dependent killing of activated B cells. These observations strongly suggest that the small fraction of activated B c ells that secrete Ig are selectively sensitive to CD95-based killing b ut resistant to CD95-independent killing, This finding may help explai n why clinical autoimmunity associated with increased titers of autoan tibodies is a predominant feature of defects in CD95 or CD95 ligand.