ABSTRACT
The monoallelic expression of antigen receptor (AgR) genes, called allelic exclusion, is fundamental for highly specific immune responses to pathogens. This cardinal feature of adaptive immunity is achieved by the assembly of a functional AgR gene on one allele, with subsequent feedback inhibition of V(D)J recombination on the other allele. A range of epigenetic mechanisms have been implicated in sequential recombination of AgR alleles; however, we now demonstrate that a genetic mechanism controls this process for Tcrb. Replacement of V(D)J recombinase targets at two different mouse Vß gene segments with a higher quality target elevates Vß rearrangement frequency before feedback inhibition, dramatically increasing the frequency of T cells with TCRß chains derived from both Tcrb alleles. Thus, TCRß allelic exclusion is enforced genetically by the low quality of Vß recombinase targets that stochastically restrict the production of two functional rearrangements before feedback inhibition silences one allele.