A key role for BAFF in maintaining peripheral B cells

Abstract

In mice, only a few percent of B cells produced in the bone marrow (BM) enter the peripheral long-lived mature B-cell pool. Selection for entry into the periphery occurs in the BM and spleen. The majority of immature cells is thought to die in the BM owing to the expression of autoreactive B-cell receptor (BCR) specificities. Immature cells that survive this initial selection migrate to the spleen as transitional-stage T1 B cells (IgMhiIgD−), which differentiate to a second transitional stage (T2) marked by the high-level expression of IgD. T2 B cells are found in splenic primary follicles and are the direct precursors of mature B cells. Also, they are the targets of further selection; survival of T2 cells depends on signals generated through the BCR but, also, on undefined factors derived from the microenvironment of the adult spleen. Three recent papers suggest that the B-cell-activating factor belonging to the tumor necrosis factor (TNF) family (BAFF) 1xAn essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Schiemann, B. et al. Science. 2001; 293: 2111–2114Crossref | PubMed | Scopus (706)See all References, 2xTACI-Ig neutralizes molecules critical for B-cell development and autoimmune disease. Impaired B-cell maturation in mice lacking BlyS. Gross, J.A. et al. Immunity. 2001; 15: 289–302Abstract | Full Text | Full Text PDF | PubMed | Scopus (449)See all References and a newly identified BAFF receptor (BAFF-R) 3xBAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Thompson, J.S. et al. Science. 2001; 293: 2108–2111Crossref | PubMed | Scopus (619)See all References3 form a crucial ligand–receptor pair that facilitates the survival of transitional B cells and, thereby, maintenance of mature B cells.BAFF (also called Blys or TNFS13B), which is expressed and secreted by a variety of cells, including macrophages, dendritic cells and T cells, was identified first as a powerful co-stimulator of B-cell proliferation and Ig production. Then, it was discovered that the over-expression of BAFF results in vastly increased numbers of mature, but not immature, B cells. The occurrence of autoantibodies (and resultant autoimmune disease), with similar characteristics to those found in human systemic lupus erythematosus (SLE), in BAFF-transgenic mice further suggested a role for BAFF in regulating the maintenance of mature B cells. Hitherto, BAFF had been shown to bind to two members of the TNF receptor family – BCMA, which is B-cell-restricted, and TACI, which is expressed not only on a subset of B cells but, also, on activated T cells. However, studies of these receptors in knockout mice suggest that BCMA and TACI do not mediate the survival activity of BAFF; BCMA-deficient animals have a normal phenotype, whereas TACI-knockouts have increased numbers of mature B cells and immunoglobulins.This paradox has now been resolved by Thompson et al.3xBAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Thompson, J.S. et al. Science. 2001; 293: 2108–2111Crossref | PubMed | Scopus (619)See all References3 who, by screening an expression library with BAFF, have identified a third receptor, BAFF-R, which is not only B-cell specific but does not bind any other known TNF-family ligand. Furthermore, Schiemann et al.1xAn essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Schiemann, B. et al. Science. 2001; 293: 2111–2114Crossref | PubMed | Scopus (706)See all References1 and Gross et al.2xTACI-Ig neutralizes molecules critical for B-cell development and autoimmune disease. Impaired B-cell maturation in mice lacking BlyS. Gross, J.A. et al. Immunity. 2001; 15: 289–302Abstract | Full Text | Full Text PDF | PubMed | Scopus (449)See all References2 have reported independently that BAFF-deficient mice show an almost complete loss of follicular and marginal-zone (MZ) B cells, whereas immature B cells are unaffected. Crucially, the developmental block in BAFF-knockout mice occurs at the transitional T1 stage, suggesting that transitional T2 B cells are the primary target for BAFF or T1 cells require BAFF for differentiation to the T2 stage. B1 B cells were unaffected in BAFF-deficient mice; therefore, it appears that B1 B cells are maintained independently of BAFF. Underlining the importance of BAFF–BAFF-R in the maintenance of mature follicular and MZ B cells, Thompson et al.3xBAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Thompson, J.S. et al. Science. 2001; 293: 2108–2111Crossref | PubMed | Scopus (619)See all References3 report also that the immunodeficient mouse strain A/WySnJ, which has a phenotype similar to that of BAFF-deficient mice, has a mutation in the gene encoding BAFF-R.In addition to furthering our understanding of B-cell development, these studies raise the question of whether excessive signaling through BAFF-R can allow survival in the periphery of autoreactive mature B cells – especially, as increased levels of BAFF have been reported in SLE. Also, it will be interesting to determine whether BAFF plays a role in the survival of Ag-activated and memory B cells.