Fig. 8.4 The development of a B-lineage cell proceeds through several stages marked by the rearrangement and expression of the immunoglobulin genes. The stem cell has not yet begun to rearrange its immunoglobulin (Ig) gene segments; they are in the germline configuration found in all nonlymphoid cells. The heavy-chain (H-chain) locus rearranges first. Rearrangement of a D gene segment to a JH gene segment starts in the common lymphoid progenitor and occurs mostly in early pro-B cells, generating late pro-B cells in which VH to DJH rearrangement occurs. A successful VDJH rearrangement leads to the expression of a complete immunoglobulin heavy chain as part of the pre-B-cell receptor, which signals via Igα, Igβ, and Btk (see Fig 7.27). Once this occurs, the cell is stimulated to become a large pre-B cell, which proliferates to become small resting pre-B cells; at this point the cells cease expression of the surrogate light chains (λ5 and VpreB) and express the μ heavy chain alone in the cytoplasm. Small pre-B cells reexpress the RAG proteins and start to rearrange the light-chain (L-chain) genes. Upon successfully assembling a light-chain gene, a cell becomes an immature B cell that expresses a complete IgM molecule at the cell surface, which also signals via Igα and Igβ. Mature B cells produce a δ heavy chain as well as a μ heavy chain, by a mechanism of alternative mRNA splicing (see Fig. 5.17), and are marked by the additional appearance of IgD on the cell surface. All stages through the development of immature B cells takes place in the bone marrow; the final maturation to IgM+IgD+ mature B cells occurs in the spleen. The earliest B-lineage surface markers are CD19 and CD45R (B220 in the mouse), which are expressed throughout B-cell development. A pro-B cell is also distinguished by the expression of CD43 (a marker of unknown function), Kit (CD117), and the IL-7 receptor. A late pro-B cell starts to express CD24 (a marker of unknown function). A pre-B cell is phenotypically distinguished by the expression of the enzyme BP-1, whereas Kit is no longer expressed.
(see Section 7-20). The temporal expressions of some of the transcription factors, surface proteins, and receptors required for B-cell development are listed in Fig. 8.3 and Fig. 8.4.
Although the V(D)J recombinase system operates in both Band T-lineage cells and uses the same core enzymes, rearrangements of T-cell receptor genes do not occur in B-lineage cells, nor do complete rearrangements of immunoglobulin genes occur in T cells. The ordered rearrangement events that do occur are associated with lineage-specific low-level transcription of the gene segments about to be joined.
The initial D to JH rearrangements in the immunoglobulin heavy-chain locus (Fig. 8.5) typically occur on both alleles, at which point the cell becomes a late pro-B cell. Most D to JH joins in humans are potentially useful, because most human D gene segments can be translated in all three reading frames without encountering a stop codon. Thus, there is no need for a special mechanism to distinguish successful D to JH joints, and at this early stage there is also no need to ensure that only one allele undergoes rearrangement. Indeed, given the likely rate of failure at later stages, starting off with two successfully rearranged D–JH sequences may be an advantage.