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.
Hirohata
S
S
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D053222:Fas Ligand Protein; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology*; D016685:Mitomycin / Q000494:pharmacology; D016853:Muromonab-CD3 / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D019014:fas Receptor; D016685:Mitomycin; D004247:DNA