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

• Published in: European journal of immunology 2004-02, Vol.34 (2), p.509-518
• Main Authors: Tardivel, Aubry, Tinel, Antoine, Lens, Susanne, Steiner, Quynh‐Giao, Sauberli, Estelle, Wilson, Anne, Mackay, Fabienne, Rolink, Antonius G., Beermann, Friedrich, Tschopp, Jürg, Schneider, Pascal
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - immunology; B-Cell Activating Factor; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B cell subsets; Carrier Proteins - genetics; Carrier Proteins - immunology; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Differentiation - immunology; Development; Flow Cytometry; Gene Expression Regulation - immunology; IgG3; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Membrane Proteins - immunology; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - immunology; Spleen; Spleen - immunology; Transgenic mice; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324692

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‐Ig×Bcl‐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.