title: The role of CD40-CD40 ligand interactions in suppression of human B cell responsiveness by CD4+ T cells.
abstract: Although human 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 examined 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 and CD40-CD40 ligand (CD40L) interactions. The suppressive activity was assessed by the effects of mitomycin C untreated CD4+ T cells (control CD4+ T cells) activated by immobilized anti-CD3 for 72 h 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 CD4+ T cells have been shown to express functional Fas receptor. Thus, anti-Fas mAb CH11 inhibited the production of IgM and IgG induced by anti-CD3-activated mitomycin C treated CD4+ T cells 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-activated control CD4+ T cells. Anti-CD40L mAb inhibited the production of IgM and IgG stimulated with anti-CD3-activated mitomycin C treated CD4+ T cells when it was added at the initiation of cultures. By contrast, anti-CD40L mAb markedly reversed the suppression of B cell production of IgM and IgG by anti-CD3-activated control CD4+ T cells when it was added after 72 h from the initiation of cultures. Consistently, the extent and intensity of CD40L on anti-CD3-stimulated CD4+ T cells declined upon treatment with mitomycin C in parallel with the loss of suppressive activities on B cell responses. These results indicate that signals achieved by direct interactions through CD40-CD40L exert bidirectional effects on the outcome of humoral immune responses depending on the state of activation of B cells and on the extent of CD40 ligation. Moreover, the data suggest that CD40-CD40L interactions rather than Fas-FasL interactions may play more critical roles in direct cellular collaboration between B cells and anti-CD3 stimulated CD4+ T cells to prevent the extension of responses of inappropriately activated B cells.
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hirohata
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000276:immunology*; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D002450:Cell Communication / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D007108:Immune Tolerance; D007136:Immunoglobulins / Q000096:biosynthesis; D066298:In Vitro Techniques; D007700:Kinetics; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D019013:CD40 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D019014:fas Receptor; D023201:CD40 Ligand