Receptor editing in lymphocyte development and central tolerance

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Abstract
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.