B Cell Development and Generation of Lymphocyte Diversity

Questions for class discussion

For a cell to become a B cell, it must perform somatic recombination of V-D-J gene segments to encode a complete V_H and V-J gene segments to encode a complete V_L.

The first and second hypervariable regions are encoded within each V_H or VL gene segment, while the third hypervariable region is encoded by V_H + D_H + J_H or V_L + J_L Nucleotides added at the junctions during recombination increase the hypervariability of the third hypervariable region.

B cell development occurs in the bone marrow. Binding signals to growth factor receptors and later to the pre-B receptor signal the cell to express RAG/TdT enzymes to bind, cut, add nucleotides, and splice the H chain and L chain DNA into genes for V_H and V_L. The RAG enzymes "read" the DNA sequences between the V, D and J genes to make the proper splices. TdT can add nucleotides at the joins to lengthen the genes.

A productive rearrangement means that a receptor is expressed on the cell membrane and receives the appropriate binding signal for the cell to go to the next step. If no receptor is expressed, the cell dies. Nonproductive rearrangements occur when the random cutting and nucleotide addition results in a frame shift mutation that introduces a stop codon.

In B cell development, H chain genes are rearranged first, followed by L chain genes. B cells have two chances to rearrange H chain genes and 4 chances to rearrange L chain genes.

Overview of B cell development, showing critical signaling steps.

Estimates of total BCR and TCR diversity made by calculating the theoretical number of ways to recombine the known gene segments and estimating the effects of nucleotide additions.

Mature naïve B cells simultaneously express both membrane IgM and membrane IgD. The presence of IgD signals the B cell to be stimulated rather than killed by antigen binding.

Upon receiving appropriate signals from T cells, B cells switch isotypes by removing C_H gene segments. The enzymes that do this are not RAG and gene recombination occurs in introns, so there are no nonproductive rearrangements during isotype switching.