BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death.
Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells.
Acosta-Rodríguez
Eva V
EV
Immunology, Department of Clinical Biochemistry, School of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.
Craxton
Andrew
A
Hendricks
Deborah W
DW
Merino
Maria C
MC
Montes
Carolina L
CL
Clark
Edward A
EA
Gruppi
Adriana
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
D053264:B-Cell Activating Factor; C491899:Fas protein, mouse; D006131:Growth Inhibitors; D008070:Lipopolysaccharides; C505720:Tnfsf13b protein, mouse; D019014:fas Receptor