Poor quality V? recombination signal sequences stochastically enforce TCR? allelic exclusion.

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 V? gene segments with a higher quality target elevates V? rearrangement frequency before feedback inhibition, dramatically increasing the frequency of T cells with TCR? chains derived from both Tcrb alleles. Thus, TCR? allelic exclusion is enforced genetically by the low quality of V? recombinase targets that stochastically restrict the production of two functional rearrangements before feedback inhibition silences one allele.

SUBMITTER: Wu GS 

PROVIDER: S-EPMC7478721 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature