CD95 (FAS)-BASED, SUPERANTIGEN-DEPENDENT, CD4(-CELL-MEDIATED DOWN-REGULATION OF HUMAN IN-VITRO IMMUNOGLOBULIN RESPONSES() T)

Naturally occurring microbial superantigens (SAg) have been implicated in several human idiopathic disorders, and a compelling argument for the role of SAg in autoantibody-associated disorders, such as systemic lupus erythematosus, has been proposed. To test the effects of SAg on human in vitro Ig responses, CD4(+) T cell + B cell cultures were sti mulated with graded doses of staphylococcal enterotoxin B (SEB). Ig-se creting cell (IgSC) responses were very weak in CD4(+) T cell + B cell cultures stimulated with SEE at the optimal mitogenic concentration ( high dose SEB; 100 ng/ml) but were strong in parallel cultures stimula ted with low dose SEE (0.01 ng/ml), High dose SEE actually enhanced B cell differentiation in the presence of CD4(+) T cell soluble helper f actors as long as the B cells were prevented from physically contactin g the CD4(+) T cells. However, when cell-cell contact between CD4(+) T cells and B cells was permitted, high dose, but not low dose, SEE pro moted increased CD4(+) T cell-mediated B cell apoptosis with resulting decreases in viable CD20(+) B cells and IgSC, High dose, but not low dose, SEE triggered increased levels of soluble CD95 ligand, and down- regulation of IgSC responses and incremental apoptosis of activated B cells were prevented by antagonist anti-CD95 mAb. This strongly sugges ts that CD4(+) T cell-mediated CD95-based killing of activated B cells plays a major role in controlling SEB-driven IgSC responses. Defects in SAg-based down-regulation may contribute to autoimmune disorders su ch as SLE.