The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF.
The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the T-independent IgG3, but not IgM, response was impaired in the TACI-IgxBcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.
Tardivel
Aubry
A
Department of Biochemistry, BIL Biomedical Research Center, University of Lausanne, Epalinges, Switzerland.
Tinel
Antoine
A
Lens
Susanne
S
Steiner
Quynh-Giao
QG
Sauberli
Estelle
E
Wilson
Anne
A
Mackay
Fabienne
F
Rolink
Antonius G
AG
Beermann
Friedrich
F
Tschopp
Jürg
J
Schneider
Pascal
P
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D053264:B-Cell Activating Factor; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha