Poor quality Vβ recombination signal sequences stochastically enforce TCRβ allelic exclusion.

The Journal of Experimental Medicine
Glendon S WuCraig H Bassing

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

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Citations

Aug 15, 2020·The Journal of Experimental Medicine·Michael S Krangel
Jul 22, 2020·Proceedings of the National Academy of Sciences of the United States of America·Glendon S Wu, Craig H Bassing
Nov 15, 2020·International Journal of Molecular Sciences·Alonso Rodríguez-CaparrósCristina Hernández-Munain

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Methods Mentioned

BETA
flow cytometry
transgenic
PCR
FCS

Software Mentioned

FlowJo
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