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  • Review Article
  • Published:

Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling

Nature Reviews Immunology volume 9, pages 195–205 (2009)Cite this article

Key Points

  • The pre-B-cell receptor (pre-BCR), which comprises two Igμ chains and two germline-encoded surrogate light chains (SLC) that are associated with the signalling subunits Igα and Igβ, is formed on pre-B cells following productive recombination of the immunoglobulin heavy chain gene. Although only transiently expressed, the pre-BCR marks an important checkpoint in B-cell development and regulates diverse processes, such as proliferation, allelic exclusion of the second heavy chain allele, termination of SLC expression and initiation of immunoglobulin light chain (IgL) gene recombination.

  • Downstream of the pre-BCR, SYK (spleen tyrosine kinase) has a central role in the activation of pathways that regulate the proliferation and differentiation of pre-B cells. In the context of proliferation, SYK promotes the activation of the lipid-modifying kinase phosphoinositide 3 kinase (PI3K) and its downstream mediator protein kinase B (PKB). In addition, SYK mediates differentiation through the adaptor protein SH2-domain-containing leukocyte protein of 65 kDa (SLP65), which induces the activation of IgL gene recombination.

  • Pre-BCR signalling through PI3K–PKB inhibits IgL gene recombination by inactivating the forkhead box class O (FOXO) family of transcription factors, which were recently reported to activate the RAG (recombination-activating gene) machinery and V(D)J recombination of the IgL gene. SLP65 decreases PKB activity in pre-B cells and reduces the inhibitory phosphorylation of FOXO proteins, thereby providing a molecular link between pre-BCR signalling and IgL gene recombination.

  • V(D)J recombination is tightly linked to G0 and G1 phases of the cell cycle, as the recurrence of double-stranded breaks during DNA replication or mitosis could compromise genetic integrity. This link is mainly mediated at the level of RAG2 regulation, which accumulates during G1 and is periodically degraded on S phase entry.

  • Cell cycle progression at the G1 to S phase transition is regulated by the concerted action of diverse factors, including cyclin-dependent kinase (CDK)–cyclin complexes and their inhibitors. Important cell cycle regulators, such as the CDK inhibitor p27, the retinoblastoma family protein p130 and D-type cyclins, have been shown to be direct targets of FOXO activity, suggesting that FOXO proteins not only induce RAG gene expression, but also determine a cell cycle state that enables RAG complex stability and V(D)J recombination.

Abstract

The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy chain gene. Signals through the pre-BCR are required for initiating diverse processes in pre-B cells, including proliferation and recombination of the light chain gene, which eventually lead to the differentiation of pre-B cells to immature B cells. However, the molecular mechanisms by which the pre-BCR promotes these processes remain largely unresolved. Recent findings suggest that forkhead box O (FOXO) transcription factors connect pre-BCR signalling to the activation of the recombination machinery. In this Review, we discuss how FOXO transcription factors are regulated by the pre-BCR to allow the progression of the cell cycle and the recombination of the light chain gene.

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Figure 1: The pre-BCR and B-cell development.
Figure 2: The central role of SYK downstream of the pre-BCR.
Figure 3: Control of cell cycle progression by PKB and FOXO proteins.
Figure 4: Regulation of IgL gene recombination by the PI3K–PKB–FOXO pathway.

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Acknowledgements

We thank the members of our laboratories for helpful discussion. The work of H.J., M.R. and S.H. was supported by grants from the Deutsche Forschungsgemeinschaft (SFB620 and SFB746) and the Excellence Initiative of the German federal and state governments (EXC294).

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  1. Centre for Biological Signalling Studies (bioss), Albert–Ludwigs-Universität Freiburg, Albertstrasse 19, Freiburg, 79104, Germany

    Sebastian Herzog, Michael Reth & Hassan Jumaa

  2. Department of Molecular Immunology, Faculty of Biology, Albert–Ludwigs-Universität Freiburg, Stuebeweg 51, Freiburg, 79108, Germany

    Sebastian Herzog, Michael Reth & Hassan Jumaa

  3. Max–Planck Institute of Immunobiology, Stuebueweg 51, Freiburg, 79108, Germany

    Sebastian Herzog, Michael Reth & Hassan Jumaa

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Glossary

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both B- and T-cell receptors.

Recombination signal sequences

Conserved elements that constitute recognition sites for the V(D)J recombinase proteins, which are encoded by RAG1 (recombination-activating gene 1) and RAG2. They consist of a palindromic heptamer that is immediately adjacent to the coding gene segments — V (variable), D (diversity) or J (joining) — and is separated by a 12- or 23-base-pair spacer from a conserved nonamer sequence.

Non-homologous end joining

The process that joins broken DNA ends without depending on extended homology. Components of this pathway include the proteins Ku70, Ku 80, ARTEMIS, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).

μmt−/− mice

Mice that carry a stop codon in the first membrane exon of the Igμ constant region. They lack IgM+ B cells, and B-cell development is arrested before the differentiation stage at which IgD can be expressed.

Oncogene

An altered or mutant form of a proto-oncogene, which drive the proliferation of cells. Proto-oncogenes are usually involved in the control of cell growth and division.

Scaffold protein

A protein that assembles various proteins in a signalling pathway into multimolecular complexes for them to interact. Scaffold proteins are usually characterized by a large number of protein-binding domains.

Receptor editing

A molecular process that involves secondary rearrangements (mostly of the immunoglobulin light chains) that replace existing immunoglobulin molecules and generate a new antigen receptor with altered specificity.

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Herzog, S., Reth, M. & Jumaa, H. Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. Nat Rev Immunol 9, 195–205 (2009). https://doi.org/10.1038/nri2491

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