Unlike follicular and marginal zone B cells that develop from bone marrow stem cells, the majority of B-1 B cells are generated from progenitor cells found in the fetal liver (Fig. 8.13). During late fetal and early neonatal stages in mice, B-1 B cells are produced in large numbers. After birth, the development of follicular and marginal zone B cells predominates, and few B-1 B cells are made. Current evidence indicates that the progenitor cells giving rise to B-1 B cells are committed to this lineage, and are distinct from those producing B-2 B cells. Whereas B-2 B cells are absent in mice lacking BAFF or the BAFF-R, these deficiencies have no effect on the development or survival of B-1 B cells. Additionally, the weak B-cell receptor signals that promote the final stages of B-2 B-cell maturation in the spleen require the non-canonical NF-κB activation pathway (see Section 7-23), a signaling pathway that is dispensable for B-1 B-cell development. Cytokine requirements also differ between these developmental pathways. B-1 B cells develop normally in mice lacking IL-7 or IL-7R signaling components, defects that prevent the development of B-2 B cells. B-2 B-cell development also requires the transcription factor PU.1, which is not needed for the development of B-1 B cells.
Summary.
In this section, we have followed B-cell development from the earliest progenitors in the bone marrow to the long-lived mature peripheral B-cell pool (Fig. 8.14). The heavy-chain locus is rearranged first and, if this is successful, a μ heavy chain is produced that combines with surrogate light chains to form the pre-B-cell receptor; this is the first checkpoint in B-cell development. Production of the pre-B-cell receptor signals successful heavy-chain gene rearrangement and causes cessation of this rearrangement, thus enforcing allelic exclusion. It also initiates pre-B-cell proliferation, generating numerous progeny in which subsequent light-chain rearrangement can be attempted. If the initial light-chain gene rearrangement is productive, a complete immunoglobulin B-cell receptor is formed, gene rearrangement again ceases, and the B cell continues its development. If the first light-chain gene rearrangement is unsuccessful, rearrangement continues until either a productive rearrangement is made or all available J regions are used up. If no productive rearrangement is made, the developing B cell dies. Once a complete immunoglobulin receptor is expressed on the surface of the cell, immature B cells undergo tolerance to self antigens. This process begins in the bone marrow and continues for a short time after immature B cells emigrate to the periphery. For the majority population of B cells, the final stages of their maturation occur in the B-cell follicles of the spleen, and require the TNF family member BAFF as well as signals through the B-cell receptor.