Allelic Exclusion, Isotypic Exclusion, and the Developmental Regulation of V(D)J Recombination
© 2003 Elsevier Ltd. All rights reserved. This chapter focuses on the various mechanisms that impart developmental control to V(D)J recombination and that yield allelically and isotypically excluded antigen receptor repertoires. The lymphoid specificity of V(D)J recombination reflects the regulated expression of recombinase proteins RAG1 and RAG2. Variation in RAG gene expression and protein stability accounts for the two waves of V(D)J recombination events in developing B and T lymphocytes However, neither RAG gene expression nor the RSS constraints can account for the locus-specific developmental control of V(D)J recombination. Rather, developmental control is thought to occur largely through regulation of RAG protein access to RSSs within chromatin. Transcriptional enhancers appear to function, at least in part, by activating germline promoters. These promoters then appear to influence V(D)J recombination in a relatively localized fashion. TCRβ, like IgH, is subject to stringent allelic exclusion, with the product of a functional rearrangement providing a potent feedback signal that blocks further rearrangement at the V-to-DJ step. Co-expression of two functional TCRβ proteins has been detected, but occurs rarely. Available evidence suggests that TCRβ allelic exclusion is associated with changes in Vβ but not DβJβCβ chromatin. TCRα, the TCRγ, and TCRδ genes rearrange without evidence of allelic exclusion. B cells are isotypically excluded in that they usually express κ or λ light chains, but not both. The isotypic exclusion reflects a defined developmental sequence of light chain rearrangement, with κ preceding λ, or with a much higher probability of κ rearrangement.
Krangel, MS; Schlissel, MS
- Molecular Biology of B Cells
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International Standard Book Number 13 (ISBN-13)
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