DIFFERENTIAL HUMAN T-CELL-DEPENDENT B-CELL DIFFERENTIATION-INDUCED BYSTAPHYLOCOCCAL SUPERANTIGENS (SAG) - REGULATORY ROLE FOR SAG-DEPENDENT B-CELL CYTOLYSIS

Microbial superantigens (SAg), by virtue of their binding to TCR V bet a elements and to class II MHC molecules on accessory cells, trigger T cell proliferation in a dose-dependent fashion. In contrast, SAg-indu ced T cell-dependent B cell differentiation occurs only at SAg concent rations that are orders of magnitude lower that those required for opt imal mitogenesis (low-dose SAg). At optimal mitogenic doses (high-dose SAg), SAg-driven B cell differentiation does not ensue. In this repor t, we demonstrate that this dichotomy in SAg-driven B cell differentia tion is due to the active inhibition of B cell differentiation by high -dose SAg. Such inhibition is not reversed by feeding cultures with fr esh medium, with conditioned media, or with IL2 +/- IL4, and impaired B cell differentiation is observed in cultures containing purified T c ells or CD4(+) T cells + B cells, as well as in PBMC cultures. Althoug h preincubation of either T cells or B cells with high-dose SAg impair s subsequent SAg-induced B cell differentiation, high-dose SAg is not toxic per se, since high-dose SAg does promote vigorous B cell differe ntiation in cultures of mitomycin C-treated T cells + B cells and does not inhibit T cell-independent B cell differentiation. No correlation exists between SAg-induced B cell surface expression of CTLA4 ligand and generation of Ig-secreting cells, but the dose of SAg does correla te with T cell-mediated SAg-dependent cytolysis of transformed B cell targets or autologous nontransformed activated B cell targets. B cell recovery from cultures stimulated with high-dose SAg is lower than tha t from cultures stimulated with low-dose SAg, whereas B cell apoptosis is greater in the former cultures than that in the latter cultures. T cells stimulated with high-dose SAg do not inhibit differentiation of activated B cells in the absence of physical contact between the T ce lls and the target B cells, supporting the notion of direct killing of activated B cells by T cells. The ability of low doses of SAg to prom ote B cell differentiation without generating biologically meaningful cytolytic activity and the ability of higher doses of SAg to modulate Ig production may have important pathogenetic and therapeutic ramifica tions for certain autoimmune disorders, such as systemic lupus erythem atosus.