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Nat Immunol. 2008 Jul;9(7):802-9. doi: 10.1038/ni.1624. Epub 2008 Jun 8.

Initiation of allelic exclusion by stochastic interaction of Tcrb alleles with repressive nuclear compartments.

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1
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Abstract

Studies of antigen-receptor loci have linked directed monoallelic association with pericentromeric heterochromatin to the initiation or maintenance of allelic exclusion. Here we provide evidence for a fundamentally different basis for T cell antigen receptor-beta (Tcrb) allelic exclusion. Using three-dimensional immunofluorescence in situ hybridization, we found that germline Tcrb alleles associated stochastically and at high frequency with the nuclear lamina or with pericentromeric heterochromatin in developing thymocytes and that such interactions inhibited variable-to-diversity-joining (V(beta)-to-D(beta)J(beta)) recombination before beta-selection. The introduction of an ectopic enhancer into Tcrb resulted in fewer such interactions and impaired allelic exclusion. We propose that initial V(beta)-to-D(beta)J(beta) recombination events are generally monoallelic in developing thymocytes because of frequent stochastic, rather than directed, interactions of Tcrb alleles with repressive nuclear compartments. Such interactions may be essential for Tcrb allelic exclusion.

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PMID:
18536719
PMCID:
PMC2561338
DOI:
10.1038/ni.1624
[Indexed for MEDLINE]
Free PMC Article

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