HUMAN T-CELL-DEPENDENT B-CELL DIFFERENTIATION-INDUCED BY STAPHYLOCOCCAL SUPERANTIGENS

Microbial superantigens (SAgs), by virtue of their binding to TCR V be ta elements on T cells and to class II MHC molecules on accessory cell s (AC), trigger T cell activation. Although anti-CD3 mAb (which also t rigger T cell activation via surface CD3/TCR) can readily induce T cel l-dependent B cell differentiation in unmanipulated PBMC cultures, ind uction of Ig production in SAg-stimulated cultures has usually require d special manipulation of the T cells, such as irradiating them or tre ating them with mitomycin C. We now demonstrate that eight different s taphylococcal SAgs, typically at concentrations 10- to 100-fold lower than those required for proliferation, can each trigger unmanipulated peripheral blood and tonsil T cells to drive polyclonal B cell differe ntiation. Such SAg-induced T cell-dependent generation of Ig-secreting cells (IgSC) requires T cells and B cells only and occurs in the abse nce of monocytes as long as there are adequate numbers of B cells to s erve as (DR(+)) AC. Physical contact among T cells, responder B cells, and AC (when different from the responder B cells) is required. The f usion protein CTLA4Ig inhibits SAg-induced IgSC generation in a dose-d ependent fashion, whereas a control fusion protein has no such effect. In contrast, CTLA4lg has, at best, only modest effects on SAg-induced T cell proliferation, indicating that CD28 (CTLA4)/B7 (B7-like) inter actions play a more prominent role in SAg-induced IgSC generation than in SAg-induced T cell proliferation. These results establish SAg-indu ced T cell-dependent B cell differentiation as a useful model for T ce ll/B cell interactions, inasmuch as no other cell types are necessary for successful B cell differentiation; these results also demonstrate the importance of CD28 (CTLA4)/B7 (B7-like)dependent mechanisms in thi s process.