Lymphocyte development is a very complex process. Our understanding of such processes is often built up gradually, much like putting together the pieces of a jigsaw puzzle. Evidence is mounting that the recently identified members of the tumour-necrosis family (TNF) superfamily, BLyS (also known as BAFF, THANK, zTNF4 and TALL-1) and APRIL (a proliferation-inducing ligand), and their receptors, transmembrane activator and CAML-interactor (TACI) and B-cell maturation protein (BCMA), are important regulators of B-cell development and function. BLyS and APRIL are very closely related, and each binds with high affinity to both TACI and BCMA. New work published in Immunity and Science now sheds further light on the role of these molecules in B-cell development.

Gross et al. and Schiemann et al. generated mice deficient in BAFF/BLyS. Phenotypic analysis of B-lymphocyte populations in these mice showed that B-cell development is arrested at the immature transitional T1 stage, and numbers of marginal zone, T2 and mature B cells are significantly reduced. Similar results were observed by Gross et al. in TACI–Ig transgenic mice and in normal mice treated with a TACI–Ig fusion protein, which can neutralize both BAFF/BLyS and APRIL. Interestingly, BAFF/BLyS-deficient mice had normal levels of B-1 B cells in the peritoneal cavity, but decreased numbers of conventional B-2 B cells. By contrast, the TACI–Ig-treated mice and TACI–Ig transgenics had reduced numbers of B-1 peritoneal B cells. These results indicate that BAFF/BLyS is not required for the development of B-1 B cells.

Initial studies by Thompson et al. on a human B-cell line indicated the existence of a third BAFF/BLyS receptor — this cell line binds with high affinity to BAFF/BLyS; however, surface expression of BCMA is not detectable and mRNA levels of TACI are low. Human BAFF receptor (BAFF-R) was isolated from an expression library and a mouse homologue was subsequently cloned. The extracellular domain of human and mouse BAFF-R contains four conserved cysteine residues, and the number and spacing of these cysteines is unique in the TNF superfamily. Transfection studies showed that human BAFF-R binds only to human and mouse BAFF/BLyS, and not to APRIL. This study also showed that A/WySnJ mice, which were previously characterized as having a similar phenotype to BAFF/BLys-deficient animals, have a mutation in the cytoplasmic tail of BAFF-R, which accounts for their lack of mature B cells.

Taken together, the results from this recent flurry of papers add further pieces to the jigsaw puzzle of our understanding of B-cell development. However, several pieces of the puzzle are still missing, and further work will be required to establish the precise roles of these molecules in B-cell development.