Role of the Transcription Factor BSAP (Pax-5) in B-Cell Development

Abstract

The development of B-lymphocytes from hematopoietic stem cells is a highly ordered and coordinated process that results in antigen-responsive B-cells with individual immunoglobulin receptors. This developmental pathway can be dissected into several stages according to the differential expression of specific cell surface markers, the distinctive growth factor requirements, and the sequential rearrangement of immunoglobulin heavy (IgH) and light (IgL) chain genes (reviewed in ref. 1). To date, two different classification schemes are in use that rely on the analysis of different sets of cell surface markers (Fig. 1). Hardy et al. (2,3) have employed the differential expression of CD43, heat stable antigen (HSA), BP-1, IgM, and IgD to divide B-cell development into seven distinct stages (A—F) (Fig. 1, bottom). Instead, Rolink et al. (4) have ordered the different B-lymphocyte subpopulations in the bone marrow by cell size and expression of c-kit,CD25, and the surrogate light chains VpreB and λ5 (Fig. 1, top). These analyses demonstrated that the earliest B-cell progenitors are large cycling cells and are in the process of DH-to-JH rearrangement of the IgH locus and can be cloned in vitro on stromal cells in the presence of IL-7. An important checkpoint in early B-cell development ensures the positive selection of those late pro-B- (pre-Bll-) cells that have completed a productive VH-to-DHJH rearrangement, and thus transiently express the µ protein as part of the preB-cell receptor complex (Fig. 1). Signaling through this pre-B-cell receptor promotes allelic exclusion at the IgH locus, triggers proliferative cell expansion and induces differentiation to small pre-B-cells, which undergo IgL (κ or λ) gene rearrangements. Immature B-cells subsequently emerge that synthesize the IgM form of the B-cell receptor and become subjected to selection by antigen. The expression of homing receptors enables these cells to populate peripheral lymphoid organs where they participate as mature B-cells in immunological reactions and undergo terminal differentiation to immunoglobulin-secreting plasma cells (reviewed in ref. 5).