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

Ryan J. Schlimgen, Karen L. Reddy, Harinder Singh, Michael S. Krangel

Research output: Contribution to journalArticlepeer-review

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-β (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 (Vβ -to-DβJβ) recombination before β-selection. The introduction of an ectopic enhancer into Tcrb resulted in fewer such interactions and impaired allelic exclusion. We propose that initial Vβ-to-Dβ Jβ 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.

Original languageEnglish (US)
Pages (from-to)802-809
Number of pages8
JournalNature Immunology
Volume9
Issue number7
DOIs
StatePublished - Jul 2008
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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