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  • Review Article
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Receptor editing in lymphocyte development and central tolerance

Key Points

  • Receptor editing occurs when a signal transmitted by an autoreactive B-cell receptor (BCR) stimulates or sustains secondary V(D)J recombinations in the gene encoding the antigen receptor, leading to alteration of the specificity of the cell. This is the dominant mechanism of tolerance induction for immature B cells. Receptor editing has also been documented for some cases of central T-cell tolerance (in the thymus). And receptor-editing-like events occur in other contexts, such as in the thymus, where intact antigen receptors can be edited as a result of there being insufficient signal strength for the cell to be positively selected, a process that is normally required to terminate recombination at the locus that encodes the α-chain of the T-cell receptor (TCRα).

  • There are many similarities between the different types of lymphocyte in the adaptive immune system (that is, B cells, αβT cells and γδ T cells) in terms of the organization and the regulation of their antigen-receptor genes. In particular, each cell type has an asymmetry in the genetic features of its two antigen-receptor chains, favouring generation of diversity in one and receptor editing in the other.

  • The heterodimeric antigen receptor of each lymphocyte type carries one receptor chain with a variable region that consists of V (variable), D (diversity) and J (joining) minigene elements, whereas the variable region of the other receptor chain is encoded by only V and J elements.

  • The asymmetry in D-element usage causes large differences in the contributions of the two chains to overall diversity, with most diversity provided by chains that contain D-element-encoded amino-acid residues.

  • During lymphocyte development, receptor chains with a D-element-encoded region are recombined and expressed at an earlier stage in development than are receptor chains that lack such a region. In precursor (pre)-T cells and precursor (pre)-B cells, the first receptor chains to be rearranged are tested by assembly with surrogate second receptor chains to generate pre-BCRs and pre-TCRs. Pre-BCR and pre-TCR signalling are important in promoting cell maturation and in preventing functional expression of both alleles.

  • The gene structure of the second receptor chain and the nonrandom hierarchy of rearrangement seem to facilitate secondary rearrangements and receptor editing.

Abstract

The specificities of lymphocytes for antigen are generated by a quasi-random process of gene rearrangement that often results in non-functional or autoreactive antigen receptors. Regulation of lymphocyte specificities involves not only the elimination of cells that display 'unsuitable' receptors for antigen but also the active genetic correction of these receptors by secondary recombination of the DNA. As I discuss here, an important mechanism for the genetic correction of antigen receptors is ongoing recombination, which leads to receptor editing. Receptor editing is probably an adaptation that is necessitated by the high probability of receptor autoreactivity. In both B cells and T cells, the genes that encode the two chains of the antigen receptor seem to be specialized to promote, on the one hand, the generation of diverse specificities and, on the other hand, the regulation of these specificities through efficient editing.

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Figure 1: Clonal-selection mechanisms versus receptor-selection mechanisms of immune tolerance.
Figure 2: General scheme of V(D)J recombination for assembly of antigen-receptor genes.
Figure 3: Asymmetry of diversity in antibodies, and the impact of immunoglobulin light-chain editing versus immunoglobulin heavy-chain variable-minigene-element replacement.
Figure 4: T-cell and B-cell developmental pathways illustrate asymmetry in the timing of recombination of antigen-receptor genes.
Figure 5: Editing versus positive selection as mutually exclusive aspects of receptor selection.

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This work was supported by a grant from the National Institutes of Health (USA).

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Glossary

γδ T cells

T cells that express T-cell receptors consisting of a γ-chain and a δ-chain. These T cells are present mainly in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses by the mucosal immune system.

Central lymphoid tissues

The tissues in which lymphocyte development takes place: for B cells, the bone marrow; and for T cells, the thymus.

Receptor selection

A feedback mechanism by which the antigen receptor of a lymphocyte can signal either to cease V(D)J recombination or to continue V(D)J recombination, thereby controlling the maintenance or the alteration of antigen-receptor specificity, respectively.

Central-tolerance mechanism

A mechanism that occurs at the level of the central lymphoid tissues and creates tolerance to self antigens. Developing B cells, in the bone marrow, and T cells, in the thymus, that strongly recognize self antigen need to undergo further rearrangement of antigen-receptor genes to become tolerant to self, otherwise they face deletion.

Recombination signal sequence

(RSS). A conserved element that is recognized by the recombinases involved in V(D)J recombination, which are encoded by recombination-activating gene 1 (RAG1) and RAG2. These sites consist of a palindromic heptamer that is immediately adjacent to the coding minigene elements — the V (variable), D (diversity) and J (joining) elements — and is separated by a 12- or 23-base-pair spacer from a relatively conserved nonamer.

Combinatorial diversity

The contribution to antigen-receptor diversity that is provided by the independent recombination of different V (variable), D (diversity) and J (joining) minigene elements and the independent association of the two receptor chains. Combinatorial diversity is usually estimated by taking the product of the number of minigene elements that can be independently associated.

Junctional diversity

The contribution to antigen-receptor diversity that is provided by variability at recombination junctions. Owing to the regulated imprecision of V(D)J-recombination mechanisms, the recombination of any two minigene elements can lead to several distinct DNA junctions. One contributor to variability at junctions is the addition of non-template-encoded (N) nucleotides by the enzyme terminal deoxynucleotidyltransferase, which is specific to progenitor (pro)-lymphocytes. Another source of variability is created by the formation and the subsequent resolution of DNA hairpins, leading to the possible addition of micro-palindrome (P) nucleotides.

Complementarity-determining regions

(CDRs). The most variable parts of immunoglobulin molecules and T-cell receptors. These regions form loops that make contact with specific ligands. There are three such regions — CDR1, CDR2 and CDR3 — in each V (variable) domain, with CDR3 arising from V(D)J recombination and therefore being the most variable CDR.

Positive selection

The survival of developing lymphocytes with 'desirable' antigen receptors is favoured by the processes of positive selection, which include cessation of V(D)J recombination and developmental progression. For double-positive (CD4+CD8+) thymocytes, positive selection is also associated with commitment to the CD4+ or CD8+ T-cell-lineage programme, including functional differentiation and permanent downregulation of the other co-receptor. For thymocytes, weak reactivity to peptide–MHC complexes displayed at the surface of cortical thymic epithelial cells is required for positive selection. For B cells, however, requirement for an antigen-receptor ligand has only been shown for fetal-lineage B1 cells.

Allelic exclusion

In theory, every B cell has the potential to produce two immunoglobulin heavy (IgH) chains, as well as two Igκ and two Igλ immunoglobulin light (IgL) chains: one from each chromosome. In practice, however, a B cell produces only one IgH chain and one IgL chain. The process by which the production of two different IgH or IgL chains is prevented is known as allelic exclusion. That individual B cells express only Igκ or Igλ, but not both, is sometimes called isotypic exclusion.

Deacetylation

Acetylation is a post-translational modification of chromatin components, particularly histones. It correlates with actively transcribed chromatin. Histone deacetylases have been identified as components of nuclear co-repressor complexes, which reverse the actions of histone acetyltransferases, thereby inhibiting gene transcription.

Methylation

During the rearrangement of antigen-receptor genes, only loci from which methyl groups have been removed rearrange efficiently.

Anergy

A state of non-responsiveness to antigen. Anergic T cells or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Hybridoma

A lymphocyte that has been immortalized by fusion with a tumour cell.

BCR superantigen

(B-cell-receptor superantigen). A ligand that can bind a large proportion of all BCRs. Examples include protein A of staphylococci (which binds the variable region of immunoglobulin heavy chains and the constant region of IgG) and the custom-designed macro-self antigen that binds the constant region of Igκ immunoglobulin light chains.

B1 cell

A cell with the phenotype IgMhiIgDlow macrophage receptor 1 (MAC1)+B220low CD23. These B cells are the main population of B cells found in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum. In adult mice, the B1-cell population is maintained at a constant size, owing to the self-renewing capacity of these cells. B1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.

Non-template-encoded nucleotides

(N nucleotides). Nucleotides that are not encoded by the DNA and are added at V–D (variable–diversity)-minigene-element junctions and D–J (diversity–joining)-minigene-element junctions, thereby introducing new amino acids at these junctions.

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Nemazee, D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol 6, 728–740 (2006). https://doi.org/10.1038/nri1939

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