TNF Family Member B Cell-Activating Factor (BAFF) Receptor-Dependent and -Independent Roles for BAFF in B Cell Physiology

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.

Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF

“…To simplify the data representation we refer to these as "E47" RT-PCR. Sizes of the detected PCR products were 452 (GAPDH) (Frasca et al, 2004a); 454 bp (E2A) (Frasca et al, 2004a); 606 bp (AID) (Frasca et al, 2004a;Jabara et al, 2002); 429 bp (γ 1 GLTs) (Muramatsu et al, 2000); 353 bp (γ 1 PSTs) (Muramatsu et al, 2000); 600 bp (BAFF-R) (Sasaki et al, 2004); 405 bp (TACI) (primers designed in our lab); 415 bp (BCMA) (primers designed in our lab).…”

Tolerance checkpoints in B‐cell development: Johnny B good

“…The TNF family member BAFF and one of its receptors BAFF-R play a crucial role in the developmental progression of transitional B cells into the mature B-cell compartments. This is best exemplified by the fact that BAFF-and BAFF-R-deficient mice have a very severe block at the T1 stage of B-cell development [72][73][74][75][76]. Moreover, we recently showed that BAFF-BAFF-R signaling is also required for the survival of follicular and marginal zone B cells [77].…”

BAFF and the plasticity of peripheral B cell tolerance

“…A separate study by Enzler et al showed that all major components of the non-classical NF-κB pathway are crucial for BAFF-mediated survival [26•]. Further, while knockout mice for the components of each pathway differ slightly, all are essentially similar to BAFF −/− or BAFFr −/− mice [20,[34][35][36]. Thus, it seems likely that the BCR and BAFFr are coupled through these two signaling systems, either via simultaneous activation targeting separate promoters of survival, or through direct cross-talk.…”