Mechanisms of central tolerance for B cells

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Abstract

Immune tolerance hinders the potentially destructive responses of lymphocytes to host tissues. Tolerance is regulated at the stage of immature B cell development (central tolerance) by clonal deletion, involving apoptosis, and by receptor editing, which reprogrammes the specificity of B cells through secondary recombination of antibody genes. Recent mechanistic studies have begun to elucidate how these divergent mechanisms are controlled. Single-cell antibody cloning has revealed defects of B cell central tolerance in human autoimmune diseases and in several human immunodeficiency diseases caused by single gene mutations, which indicates the relevance of B cell tolerance to disease and suggests possible genetic pathways that regulate tolerance.

Key Points

  • B cell central tolerance is regulated by the mechanisms of receptor editing and apoptosis, which operate in succession over the course of 2 to 3 days.

  • Receptor editing involves ongoing immunoglobulin light chain gene recombination, leading to secondary rearrangements that can alter antigen receptor specificity by replacing one light chain with another.

  • B cell receptor (BCR) tonic signalling in immature B cells promotes the positive selection of cells with unligated receptors through a phosphoinositide 3-kinase (PI3K)-dependent pathway, whereas BCR ligation promotes negative selection, in part through hindering this pathway and probably also by downregulating BCR levels.

  • Increasing numbers of single gene defects have been described that hinder central tolerance in B cells in mice and humans

  • Novel screens for central tolerance are now possible that can be applied to mouse or human B cells, including in humanized mouse models.

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Figure 1: B cell development.
Figure 2: Antibody gene assembly by DNA recombination between gene segments.
Figure 3: B cell receptor signalling.
Figure 4: Recombination events associated with receptor editing on the immunoglobulin λ locus can silence or alter gene expression.

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Acknowledgements

The author thanks current and former members of his laboratory, The Scripps Research Institute Department of Immunology and Microbial Science, and the following funding sources: US Department of Health & Human Services, National Institutes of Health (NIH) grants R37AI059714, R01AI128836 and R01AI073148.

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Correspondence to David Nemazee.

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PowerPoint slides

Glossary

CD4+ T follicular helper (TFH) cells

CD4+ T cells that are specialized to interact with B cells to promote and maintain the germinal centre reaction.

Systemic lupus erythematosus

(SLE). A prototypical autoimmune disease characterized by B cell hyperactivity, autoantibody production and a range of symptoms that can include vasculitis, arthritis, glomerulonephritis, fever and neurological abnormalities.

Anergy

Functional impairment of B or T cells resulting from prolonged signalling, usually caused by self-recognition.

Receptor editing

A process whereby ongoing antibody gene recombination promotes a change in the specificity or expression of the antigen receptor of a B cell; receptor editing is usually associated with central tolerance.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). Conserved motifs (YXXL/IX(6–8)YXXL/I) on the cytoplasmic tails of CD79A–CD79B, CD3 proteins and other immune system proteins that become phosphorylated upon receptor ligation and recruit SYK and ZAP70.

Allelic exclusion

The phenomenon of expression of only one of two alleles despite the genetic potential to express both. In normal B cells, expression of both alleles of the heavy chain occurs at a frequency of 0.0001%, and the frequency of light-chain double expression is 1%.

Positive selection

In the context of B cell development, this refers to the process whereby immature B cells progress from a programme of active light chain gene recombination to a more mature phenotype, which is associated with the cessation of recombination and migration from bone marrow.

Tonic signal

The weak signal emanating from a receptor in the absence of its ligand.

Recombination-activating genes

RAG1 and RAG2 have non-redundant roles in initiating V(D)J recombination at recombination signal sequences through their DNA binding and nuclease activities.

Pre-BCR

(Pre-B cell receptor). The complex formed when an immunoglobulin heavy chain pairs with the surrogate light-chain components 5 and Vpre-B, allowing surface expression of a complex including CD79A–CD79B and other signalling components.

BCR capping

(B cell receptor capping). Theprocess whereby antigen receptors on B cells redistribute and aggregate on the plasma membrane after antigen recognition.

IgM macroself mice

Transgenic mice expressing a custom-designed superantigen reactive to the constant region of IgM, derived from a fusion protein of single-chain antibody fused to a part of the IgG extracellular region and transmembrane and cytoplasmic regions of an MHC class I molecule.

MicroRNAs

(miRNAs). Short (22 bp) RNAs that function by downregulating mRNA translation or stability and that have important roles in many cellular pathways.

Humanized mice

Severe combined immunodeficient (SCID) mice transplanted with haematopoietic cells from humans. These mice are useful for carrying out experiments on human immune cells in vivo.

λ-Locus excision circles

Intervening DNA removed and religated to itself by V-to-J rearrangement in the immunoglobulin λ locus.

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Nemazee, D. Mechanisms of central tolerance for B cells. Nat Rev Immunol 17, 281–294 (2017) doi:10.1038/nri.2017.19

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