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  • Review Article
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Decision making in the immune system

Regulation of B-cell fate by antigen-receptor signals

Nature Reviews Immunology volume 2, pages 945–956 (2002)Cite this article

Key Points

  • B cells are instructed continuously by B-cell receptor (BCR) signals to make crucial cell-fate decisions at several checkpoints during their development.

  • Protein tyrosine kinases, such as LYN, SYK and BTK, and effector enzymes, such as phosphatidylinositol 3-kinase (PI3K) and phospholipase Cγ2, have crucial roles in the BCR-induced activation of transcription factors, including nuclear factor-κB (NF-κB) and nuclear factor of activated T cells, that are important for B-cell fate decisions. Moreover, BCR signalling is integrated by adaptors in B cells and fine-tuned by co-receptors on B cells.

  • The BCR induces the signals that are required for survival and proliferation of B cells. These include activation of PI3K-regulated AKT, RAS–RAF–ERK (extracellular signal-regulated kinase) and NF-κB pathways.

  • Immature B cells are eliminated by negative selection (BCR-induced cell death) or inactivated (anergy), or they revise the specificity of their BCRs (receptor editing).

  • Transitional B cells can be divided into two subsets — transitional type 1 (T1) and T2. The T1 to T2 transition is a crucial event in the spleen; BCR signals facilitate T2-cell generation, and signals through the BCR and B-cell activating factor of the tumour-necrosis-factor family (BAFF) maintain the survival of T2 cells by, for example, enhancing NF-κB activation.

  • Different strengths of BCR signalling are required for the development of the three mature B-cell subsets; peritoneal B cells require the strongest BCR signal, follicular B cells require an intermediate BCR signal, and marginal-zone B cells require a weaker BCR signal.

  • B-cell fate is determined by the balance between survival and death signals initiated through the BCR.

Abstract

Recent evidence indicates that B cells are instructed continuously by B-cell receptor (BCR) signals to make crucial cell-fate decisions at several checkpoints during their development. Targeted disruption of BCR signalling components leads to distinct blocks in B-cell maturation, which indicates that key kinases and adaptors fine-tune BCR signalling to direct appropriate cell fates. Recent progress in unravelling the molecular mechanisms of the BCR signalling pathways has helped to clarify how BCR signals regulate the proliferation, survival and apoptosis of developing B cells.

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Figure 1: BCR-induced signal-transduction pathways.
Figure 2: BCR-induced cell death, survival and proliferation.
Figure 3: Development of transitional and mature B cells.
Figure 4: Model of how BCR signalling might direct B-cell fate at the immature and mature stages.

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Acknowledgements

Our work in this review was supported by grants from the National Institutes of Health. We would like to thank D. J. Rawlings and J. Braun for communicating unpublished data, and J. D. Graves, A. Craxton and T. M. Yankee for critical reading of this manuscript.

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Authors and Affiliations

  1. Departments of Microbiology and Immunology, University of Washington, Seattle, 98195, Washington, USA

    Hiroaki Niiro & Edward A. Clark

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  1. Hiroaki Niiro
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Correspondence to Edward A. Clark.

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DATABASES

LocusLink

Aiolos

AKT

BAD

BAFF

BAFFR

BAM32

BCL-2

BCL-XL

BCMA

BLK

BLNK

BTK

caspase-3

caspase-7

caspase-9

CD21

CD22

CD23

cyclin D2

ERK

FGR

FYN

GAB

GRB2

GRPL

GSK3

HCK

IgD

IgM

Igα

Igβ

IKKβ

IL-4

LYN

NEMO

NF-κB

NIK

p38 MAPK

PI3K

PIRB

PKC

PLCγ2

Raf1

Rag2

RELA

RELB

SH2D1A

SHIP

SHP1

SYK

TACI

VAV1

VAV2

VAV3

Glossary

DT40 CELLS

A chicken B-cell line that undergoes homologous recombination at a high frequency, and so is a system to generate knockout mutants in vitro to study B-cell biology.

GERMINAL CENTRES

Located in peripheral lymphoid tissues (for example, the spleen), these structures are sites of B-cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.

LIPID RAFTS

Cholesterol-rich regions that provide an ordered structure to the lipid bilayer and can include or exclude specific signalling molecules and complexes.

FOLLICULAR B CELL

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

MARGINAL-ZONE B CELL

A static, mature B-cell subset that is enriched primarily in the marginal zone of the spleen.

PERITONEAL B CELL

A mature B-cell subset in the peritoneal cavity that is enriched with a unique population of B cells known as B1 cells that recirculate between the blood and body cavities.

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Niiro, H., Clark, E. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2, 945–956 (2002). https://doi.org/10.1038/nri955

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