TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology.
The cytokine TNF family member B cell-activating factor (BAFF; also termed BLyS) is essential for B cell generation and maintenance. Three receptors have been identified that bind to BAFF: transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); B cell maturation Ag (BCMA); and BAFF-R. Recently, it was shown that A/WySnJ mice, which contain a dramatically reduced peripheral B cell compartment due to decreased B cell life span, express a mutant BAFF-R. This finding, together with normal or enhanced B cell generation in mice deficient for BCMA or TACI, respectively, suggested that the interaction of BAFF with BAFF-R triggers signals essential for the generation and maintenance of mature B cells. However, B cells in mice deficient for BAFF differ phenotypically and functionally from A/WySnJ B cells. Residual signaling through the mutant BAFF-R could account for these differences. Alternatively, dominant-negative interference by the mutant receptor could lead to an overestimation of the importance of BAFF-R. To resolve this issue, we generated BAFF-R-null mice. Baff-r(-/-) mice display strongly reduced late transitional and follicular B cell numbers and are essentially devoid of marginal zone B cells. Overexpression of Bcl-2 rescues mature B cell development in Baff-r(-/-) mice, suggesting that BAFF-R mediates a survival signal. CD21 and CD23 surface expression are reduced on mature Baff-r(-/-) B cells, but not to the same extent as on mature B cells in BAFF-deficient mice. In addition, we found that Baff-r(-/-) mice mount significant, but reduced, Ag-specific Ab responses and are able to form spontaneous germinal centers in mesenteric lymph nodes. The reduction in Ab titers correlates with the reduced B cell numbers in the mutant mice.
CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA. sasaki@cbr.med.harvard.edu
Yoshiteru
Y
Sasaki
Stefano
S
Casola
Jeffery L
JL
Kutok
Klaus
K
Rajewsky
Marc
M
Schmidt-Supprian
D000818:Animals; D000917:Antibody Formation; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology; D007107:Immune System / Q000254:growth & development*; D007136:Immunoglobulins / Q000097:blood; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D017464:Receptors, Complement 3d / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D053264:B-Cell Activating Factor; D007136:Immunoglobulins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017464:Receptors, Complement 3d; D017455:Receptors, IgE; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha