CD95 (Fas)-based, superantigen-dependent, CD4+ T cell-mediated down-regulation of human in vitro immunoglobulin responses.
Naturally occurring microbial superantigens (SAg) have been implicated in several human idiopathic disorders, and a compelling argument for the role of SAg in autoantibody-associated disorders, such as systemic lupus erythematosus, has been proposed. To test the effects of SAg on human in vitro Ig responses, CD4+ T cell + B cell cultures were stimulated with graded doses of staphylococcal enterotoxin B (SEB). Ig-secreting cell (IgSC) responses were very weak in CD4+ T cell + B cell cultures stimulated with SEB at the optimal mitogenic concentration (high dose SEB; 100 ng/ml) but were strong in parallel cultures stimulated with low dose SEB (0.01 ng/ml). High dose SEB actually enhanced B cell differentiation in the presence of CD4+ T cell soluble helper factors as long as the B cells were prevented from physically contacting the CD4+ T cells. However, when cell-cell contact between CD4+ T cells and B cells was permitted, high dose, but not low dose, SEB promoted increased CD4+ T cell-mediated B cell apoptosis with resulting decreases in viable CD20+ B cells and IgSC. High dose, but not low dose, SEB triggered increased levels of soluble CD95 ligand, and down-regulation of IgSC responses and incremental apoptosis of activated B cells were prevented by antagonist anti-CD95 mAb. This strongly suggests that CD4+ T cell-mediated CD95-based killing of activated B cells plays a major role in controlling SEB-driven IgSC responses. Defects in SAg-based down-regulation may contribute to autoimmune disorders such as SLE.
Stohl
W
W
Department of Medicine, University of Southern California, Los Angeles 90033, USA. stohl@hsc.usc.edu
Elliott
J E
JE
Lynch
D H
DH
Kiener
P A
PA
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002474:Cell-Free System; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D004768:Enterotoxins / Q000494:pharmacology; D053222:Fas Ligand Protein; D006462:Hemolytic Plaque Technique; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation / Q000276:immunology; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000494:pharmacology*; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D004768:Enterotoxins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007136:Immunoglobulins; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D018089:Superantigens; D019014:fas Receptor; C031818:enterotoxin B, staphylococcal