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

Abstract

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 Tindependent 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.

B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans

“…In addition, the analysis of BAFF Ϫ/Ϫ and of BAFF-RϪ/Ϫ mice has clearly demonstrated that B1 B cells can develop independently from BAFF-R function (5)(6)(7)(8)(30)(31)(32)(33)(34)(35)(36)(37). However, our analysis of blood B cells from both BAFF-R-deficient individuals did not reveal a corresponding B-cell subset in humans.…”

The role of APRIL and BAFF in lymphocyte activation

“…Marginal zone B cell formation also appears to be exquisitely dependent on BAFF-R-mediated signals [40,41].…”

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

“…16 This finding is in line with the broad survival function of BAFF described for both transitional and mature B cells, 17,18 and with the fact that BAFF can be functionally replaced by enforced expression of the antiapoptotic factor Bcl-2 in B cells, further pointing to its pro-survival function. 19 BAFF-R deficiency recapitulates most of the phenotype of BAFF-deficient mice but affects T-dependent and -independent humoral responses less severely, 20 suggesting that, although BAFF-R transmits important BAFF signals, there are other functional receptors for BAFF in vivo.…”