Fas ligation induces apoptosis of CD40-activated human B lymphocytes.
Since CD40/CD40 ligand (CD40Lig) interactions are essential in vivo for the generation of germinal center B cells that express Fas (Apo-1/CD95), we explored whether CD40 engagement may modulate Fas expression and function on human B lymphocytes. Resting tonsil B cells, isolated by density gradient centrifugation, express either absent or low levels of Fas. They could be induced to promptly express Fas after ligation of their CD40, however, using either a recombinant human CD40Lig or a cross-linked anti-CD40 mAb. In contrast, engagement of the B cell antigen receptor by immobilized anti-kappa and -lambda antibodies did not turn on Fas expression. Addition of anti-Fas mAb CH11 inhibited the later phases of CD40-induced B cell growth as a result of apoptotic cell death. Furthermore, Fas ligation inhibited proliferation and Ig secretion of CD40-activated B cells in response to recombinant cytokines such as interleukin (IL)-2, IL-4, and IL-10, as well as a cytokine-rich supernatant of phytohemagglutinin-activated T cells, indicating that none of those B cell tropic factors were able to prevent the Fas-induced death. Taken together, the present results show that engagement of CD40 antigen on B cells induces Fas expression and sensitizes them to Fas-mediated apoptosis. The delayed functional response to Fas ligation after CD40 activation may represent a way to limit the size of a specific B cell clone that is generated during T-B cell interactions.
Garrone
P
P
Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
Neidhardt
E M
EM
Garcia
E
E
Galibert
L
L
van Kooten
C
C
Banchereau
J
J
D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002455:Cell Division; D053222:Fas Ligand Protein; D006801:Humans; D007739:L Cells; D008211:Lymphocyte Cooperation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D014066:Palatine Tonsil / Q000166:cytology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
D019013:CD40 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D019014:fas Receptor; D023201:CD40 Ligand