Poor quality Vβ recombination signal sequences stochastically enforce TCRβ allelic exclusion

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 o...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 217; no. 9
Main Authors:	Wu, Glendon S, Yang-Iott, Katherine S, Klink, Morgann A, Hayer, Katharina E, Lee, Kyutae D, Bassing, Craig H
Format:	Journal Article
Language:	English
Published:	United States Rockefeller University Press 07-09-2020
Subjects:	Alleles Animals Base Sequence Feedback, Physiological Gene Expression Regulation Hybridomas Mice, Inbred C57BL Mice, Transgenic Protein Binding Protein Sorting Signals Proto-Oncogene Proteins c-fos - metabolism Receptors, Antigen, T-Cell, alpha-beta - genetics T-Lymphocytes - cytology Thymocytes - cytology V(D)J Recombination - genetics
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Disclosures: The authors declare no competing interests exist.
ISSN:	0022-1007 1540-9538
DOI:	10.1084/jem.20200412