TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology

J Immunol. 2004 Aug 15;173(4):2245-52. doi: 10.4049/jimmunol.173.4.2245.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibody Formation*
  • B-Cell Activating Factor
  • B-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Flow Cytometry
  • Germinal Center / immunology
  • Immune System / growth & development*
  • Immunoglobulins / blood
  • Immunohistochemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Proto-Oncogene Proteins c-bcl-2 / immunology
  • Receptors, Complement 3d / immunology
  • Receptors, IgE / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology*

Substances

  • B-Cell Activating Factor
  • Immunoglobulins
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Complement 3d
  • Receptors, IgE
  • Tnfsf13b protein, mouse
  • Tumor Necrosis Factor-alpha