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  • Review Article
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Transcriptional networks in developing and mature B cells

Nature Reviews Immunology volume 5, pages 497–508 (2005)Cite this article

Key Points

  • B cells are generated in the bone marrow from pluripotent haematopoietic stem cells, which can give rise to all blood-cell types.

  • The development of B cells can be divided into several stages that are identified by the expression of various cell-surface markers or other molecules, as well as by the extent of rearrangement of immunoglobulin genes. The first 'functional' B cells are known as immature B cells and are defined by expression of IgM at the cell surface.

  • Immature B cells exit the bone marrow and enter the spleen, where they further differentiate through several transitional stages and eventually become mature follicular or marginal-zone B cells. These cells can also undergo terminal differentiation to become plasma cells.

  • Along the B-cell-differentiation pathway, several check-points have been defined on the basis of genetic studies: these check-points are initial commitment to lymphocytic progenitors, specification of pre-B cells, entry to the peripheral B-cell pool, maturation of B cells and differentiation into plasma cells.

  • Many transcription factors have been identified to be crucial at the various regulatory nodes. In some cases, hierarchical networks of interdependent transcription factors have been defined; the best example is the E2A–EBF (early B-cell factor)–PAX5 (paired box protein 5) circuit, which controls commitment to pro- and pre-B cells.

  • Other networks, which control later stages of B-cell development or function, have been uncovered, but their precise 'wiring' has not yet been rigorously dissected.

Abstract

The development of B cells from haematopoietic stem cells proceeds along a highly ordered, yet flexible, pathway. At multiple steps along this pathway, cells are instructed by transcription factors on how to further differentiate, and several check-points have been identified. These check-points are initial commitment to lymphocytic progenitors, specification of pre-B cells, entry to the peripheral B-cell pool, maturation of B cells and differentiation into plasma cells. At each of these regulatory nodes, there are transcriptional networks that control the outcome, and much progress has recently been made in dissecting these networks. This article reviews our current understanding of this exciting field.

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Figure 1: B cells develop from early haematopoietic progenitors.
Figure 2: Transcription factors important for B-cell development and function.
Figure 3: The genetic control of B-cell specification and commitment in the bone marrow.
Figure 4: The genetic control of B-cell maturation and function in the periphery.

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Acknowledgements

Work in the laboratory of P.M. is supported by Novartis Research Foundation. A.G.R. is holder of the Roche Chair of Immunology, endowed by F. Hoffman-La Roche Ltd. Work in the laboratory of A.G.R. is supported by grants from the Swiss National Science Foundation. We apologize to colleagues whose articles could not be cited because of space limitations.

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Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, Basel, 4058, Switzerland

    Patrick Matthias

  2. Department of Clinical and Biological Sciences, University of Basel, Mattenstrasse 28, Basel, 4058, Switzerland

    Antonius G. Rolink

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  1. Patrick Matthias
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Correspondence to Patrick Matthias.

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DATABASES

Entrez Gene

Aiolos

E2A

EBF

Ikaros

IRF4

IRF8

LEF1

Notch-1

Notch-2

OBF1

OCT2

PAX5

PU.1

RBP-Jκ

SOX4

SPI-B

FURTHER INFORMATION

Patrick Matthias's homepage

Glossary

ALLELIC EXCLUSION

In theory, every B cell has the potential to produce two immunoglobulin heavy chains and two immunoglobulin light chains. In practice, however, a B cell produces only one immunoglobulin heavy chain and one immunoglobulin light chain. The process by which production of two different chains is prevented is known as allelic exclusion.

FOLLICULAR B CELLS

A recirculating, mature B-cell subset that populates the follicles of the spleen and lymph nodes.

MARGINAL-ZONE B CELLS

A static, mature B-cell subset that is enriched mainly in the marginal zone of the spleen, which is located at the border of the white pulp.

ETS FAMILY

A family of transcription factors that have a DNA-binding domain with homology to the avian leukosis virus E26.

ZINC-FINGER TRANSCRIPTION FACTORS

A class of transcription factors that contain a DNA-binding domain in which cysteine and histidine residues are coordinated by zinc atoms and thereby form 'fingers' that bind DNA.

CHROMATIN-REMODELLING COMPLEXES

Multiprotein complexes that are recruited to the regulatory elements of genes and remodel chromatin in an ATP-dependent manner, thereby increasing the accessibility of chromatin to molecules that regulate transcription.

DOMINANT-NEGATIVE PROTEIN

A defective protein that retains interaction capabilities and thereby distorts or competes with normal proteins.

HYPOMORPHIC

A type of mutation in which either the altered gene product has a decreased level of activity or the wild-type gene product is expressed at a decreased level.

BASIC HELIX-LOOP–HELIX GENE FAMILY

(bHLH gene family). A family that encodes transcription factors with a conserved DNA-binding domain that consists of an HLH motif, which mediates dimerization, adjacent to a basic region, which is responsible for binding to DNA.

E BOX

A DNA element with a conserved sequence that was initially found in the IgH enhancer on the basis of in vivo footprinting assays. E boxes have the consensus sequence CANNTG (where N denotes any nucleotide) and are binding sites for basic helix–loop–helix proteins.

STERILE IGH RNA

(Sterile immunoglobulin heavy-chain RNA). A transcript of an unrearranged IgH locus, which does not result in functional protein. Its presence is thought to reflect the accessibility of the locus for recombination.

HOMEODOMAIN PROTEIN

A member of a class of transcription factors that contains a DNA-binding domain with homology to the Drosophila melanogaster homeodomain regulatory proteins. This DNA-binding domain contains a helix–turn–helix motif, which was initially found in bacterial repressor proteins.

GROUCHO FAMILY

A family of transcriptional repressors that were named after the neurogenic Drosophila melanogaster gene groucho. These repressors interact with various transcription factors — such as members of the basic helix–loop–helix family, T-cell factors (TCFs) and lymphoid-enhancer-binding factor 1 (LEF1) and paired box protein 5 (PAX5) — thereby repressing the expression of target genes of these factors.

HIGH-MOBILITY GROUP BOX FAMILY

(HMG-box family). A class of transcription factors with a DNA-binding domain that has homology to a motif found in the HMG of DNA-binding proteins. Unlike most transcription factors, HMG-box proteins bind in the minor groove of DNA.

POU DOMAIN

A class of bipartite DNA-binding domains that is characterized by a carboxy-terminal variant homeodomain separated by a flexible linker from an amino-terminal POU (Pit1, Oct1, Unc86)-specific domain. Because of this unique structure, the POU domain can bind DNA when the domain itself is in many different configurations.

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Matthias, P., Rolink, A. Transcriptional networks in developing and mature B cells. Nat Rev Immunol 5, 497–508 (2005). https://doi.org/10.1038/nri1633

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  • DOI: https://doi.org/10.1038/nri1633

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