Regulation of T cell receptor beta allelic exclusion at a level beyond accessibility

Nat Immunol. 2005 Feb;6(2):189-97. doi: 10.1038/ni1157. Epub 2005 Jan 9.

Abstract

Allelic exclusion of V(beta)-to-DJ(beta) recombination depends on asynchronous rearrangement of alleles of the gene encoding T cell receptor beta in double-negative thymocytes and feedback inhibition that is maintained in double-positive thymocytes. Feedback is thought to be enforced through downregulation of V(beta) accessibility. In an attempt to override this negative regulation, we introduced the enhancer of the gene encoding T cell receptor alpha into the V(beta) gene cluster downstream of V(beta)12. In double-negative thymocytes, the introduced enhancer had no measurable effect on accessibility, but V(beta)12 rearrangement was stimulated and V(beta)12 allelic exclusion was partially subverted. In contrast, double-positive thymocytes showed increased V(beta) transcription and accessibility, but feedback inhibition of V(beta)-to-DJ(beta) recombination remained intact. Our results indicate additional regulatory constraints on V(beta)-to-DJ(beta) recombination that operate beyond the accessibility barrier.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Animals
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • Gene Rearrangement, T-Lymphocyte / genetics*
  • Histones / metabolism
  • Mice
  • Mice, Knockout
  • Nucleosomes / genetics
  • Nucleosomes / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / genetics*
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Transcription, Genetic / genetics

Substances

  • Chromatin
  • Histones
  • Nucleosomes
  • Receptors, Antigen, T-Cell, alpha-beta