The pre-TCR signal induces transcriptional silencing of the TCRγ locus by reducing the recruitment of STAT5 and Runx to transcriptional enhancers

Shizue Tani-ichi, Masanobu Satake, Koichi Ikuta

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

The mouse TCRγ locus is positively regulated by the transcription factors STAT5 and Runx. While the locus undergoes frequent rearrangements in T lymphocytes, TCRγ transcription is repressed in ab T cells. This phenomenon, known as TCRγ silencing, depends on pre-TCR-induced thymocyte proliferation. The molecular basis for TCRγ silencing, however, is largely unknown. Here, we show that pre-TCR signaling reduces transcription and histone acetylation of the TCRγ locus irrespective of V-J rearrangements. We also demonstrate that Runx is recruited to Eγ and HsA enhancer elements of the TCRγ locus, primarily at the CD- CD8- double-negative stage and that Runx binding to these elements decreases at later stages of thymocyte development. Importantly, anti-CD3 antibody treatment decreased IL-7R expression levels, STAT5 phosphorylation and recruitment of STAT5 and Runx to Eg and HsA elements in RAG2-deficient thymocytes, suggesting that pre-TCR signaling triggers reduced binding of STAT5 and Runx to the enhancer elements. Furthermore, we observed that misexpression of STAT5 or Runx in the CD4+ CD8+ double-positive cell line DPK induces TCRγ gene transcription. Finally, we showed that TCRγ transcription is induced in αβ T cells from Runx3 transgenic mice, suggesting that Runx3 counteracts TCRγ silencing in αβ T cells in vivo. Our results suggest that pre-TCR signaling indirectly inactivates TCRγ enhancers by reducing recruitment of STAT5 and Runx and imply that this effect is an important step for TCRγ silencing in αβ T cells.

Original languageEnglish
Pages (from-to)553-563
Number of pages11
JournalInternational immunology
Volume23
Issue number9
DOIs
Publication statusPublished - 2011 Sep 1

Keywords

  • Chromatin
  • IL-7
  • Transcription factor
  • V(D)J recombination
  • γδT cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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