Table 2 B-1 cell ontogeny: made or born?

There are two theories explaining B-1 cell origin. The selection model postulates that B cell progenitors are instructed to become either B-1 or B-2 based on the BCR-mediated recognition of antigens. The lineage model posits that B-1 and B-2 cells arise from different progenitors, which are committed with each particular lineage even before the expression of the BCR. Data supporting the lineage model arose from experiments showing that adult BM-derived HSCs can efficiently reconstitute B-2 [19] cells but they poorly reconstitute B-1a cells [20], whereas neonatal liver-derived cells can efficiently reconstitute the B-1 cell pool [21]. In 2006, Montecino-Rodriguez and colleagues described a specific B-1 cell precursor (Lin⁻CD93⁺CD19⁺B220^lo/neg) that was found in the fetal liver [22], which was later found in the yolk sac (YS) at day E9.5 [16]. This early hematopoietic progenitor at E9.5 preferentially generated B-1 rather than B-2 or marginal zone B cells [23]. Considering that HSCs capable to generate B-2 cells appear only at E10.5 in the AGM region, B-1 cells can be generated in a pre-HSC wave of lymphopoiesis [16]

The selection model arose after a publication by Cong and colleagues showing that splenic B cells, lacking CD5 and expressing CD23, assumed the B-1 phenotype expressing CD5 after culturing in the presence of anti-IgM and IL-6 [24]. Subsequently, Haughton et al., proposed that “B-1 cells are made, not born”, starting the hypothesis that the commitment to B-1 or B-2 lineage occurs after BCR expression and is antigen-driven [25]. In fact, the generation of CD5⁺ B-1 cells is strongly dependent on BCR signaling, since Btk-deficient Xid mice have fewer B cells in the spleen, low levels of serum IgM and completely lack CD5⁺ B-1 cells [26]. More direct evidence for the role of BCR signaling in the instruction of B-1a cells was provided by experiments using transgenic mice that naturally generated self-reactive B cells expressing a BCR that recognizes the cell-surface protein Thy-1 (CD90). While B-1a cells in mice expressing Thy-1 were efficiently generated, mice deficient for Thy-1 could not generate B-1a cells [27]. In addition, the swapping of specific BCRs in B-2 cells is sufficient to switch B-2 cells into B-1 cells in transgenic mice. The switch induces proliferative burst and the migration of these cells to the peritoneal and pleural cavities [28]