Suppression of human B cell responsiveness by CD4+ T cells does not involve CD95-CD95 ligand interactions.

Although human CD4+ T cells have been shown to regulate humoral immune responses by directly inhibiting B cells, the precise sequelae for the mechanism of suppression have not yet been delineated. The present study was therefore designed to explore the nature of T cell-B cell collaboration to suppress B cell responses. Special attention was directed to the roles of Fas (CD95)-Fas ligand (FasL) interactions. The suppressive activity was assessed by the effects of mitomycin C-untreated CD4+ T cells activated by immobilized anti-CD3 for 72 h (CD4+ suppressors) on the production of IgM and IgG of B cells stimulated for 72 h with immobilized anti-CD3-activated mitomycin C-treated CD4+ T cells. In this model system, B cells stimulated with anti-CD3-activated mitomycin C-treated CD4+ T cells expressed functional Fas receptors. Accordingly, addition of anti-Fas mAb CH-11 inhibited the cluster formation and differentiation of activated B cells as a result of apoptotic cell death in a manner that was completely reversed by a neutralizing anti-Fas mAb ZB4. However, neither ZB4 nor anti-FasL mAb reversed the suppression of B cell responses by anti-CD3-induced CD4+ suppressors. Of interest, ZB4 significantly enhanced the production of IgM and IgG induced by anti-CD3-activated mitomycin C-treated CD4+ T cells in the absence of CD4+ suppressors. Consistently, mitomycin C-treated CD4+ T cells as well as mitomycin C-untreated CD4+ T cells expressed comparable levels of FasL upon activation with immobilized anti-CD3, although their intensities were very modest. These results indicate that B cells activated with anti-CD3-stimulated CD4+ T cells express functional Fas receptors and are sensitive to Fas-mediated apoptosis. However, the data also suggest that interactions other than Fas-FasL may play a critical role in direct cellular collaboration between activated B cells and anti-CD3-induced CD4+ suppressors to inhibit B cell responses.