Poor Quality Vβ Recombination Signal Sequences Enforce TCRβ Allelic Exclusion by Limiting the Frequency of Vβ Recombination

Abstract

SUMMARYMonoallelic expression (allelic exclusion) of T and B lymphocyte antigen receptor genes is achieved by the assembly of a functional gene through V(D)J recombination on one allele and subsequent feedback inhibition of recombination on the other allele. There has been no validated mechanism for how only one allele of any antigen receptor locus assembles a functional gene prior to feedback inhibition. Here, we demonstrate that replacement of a single Vβ recombination signal sequence (RSS) with a better RSS increases Vβ rearrangement, revealsTcrballeles compete for utilization in the αβ T cell receptor (TCR) repertoire, and elevates the fraction of αβ T cells expressing TCRβ protein from both alleles. The data indicate that poor qualities of Vβ RSSs for recombination with Dβ and Jβ RSSs enforces allelic exclusion by stochastically limiting the incidence of functional Vβ rearrangements on both alleles before feedback inhibition terminates Vβ recombination.