Thymocyte Proliferation Induced by Pre-T Cell Receptor Signaling Is Maintained through Polycomb Gene Product Bmi-1-Mediated Cdkn2a Repression

Masaki Miyazaki, Kazuko Miyazaki, Manami Itoi, Yuko Katoh, Yun Guo, Rieko Kanno, Yuko Katoh-Fukui, Hiroaki Honda, Takashi Amagai, Maarten van Lohuizen, Hiroshi Kawamoto, Masamoto Kanno

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Thymocytes undergo massive proliferation before T cell receptor (TCR) gene rearrangement, ensuring the diversification of the TCR repertoire. Because activated cells are more susceptible to damage, cell-death restraint as well as promotion of cell-cycle progression is considered important for adequate cell growth. Although the molecular mechanism of pre-TCR-induced proliferation has been examined, the mechanisms of protection against cell death during the proliferation phase remain unknown. Here we show that the survival of activated pre-T cells induced by pre-TCR signaling required the Polycomb group (PcG) gene product Bmi-1-mediated repression of Cdkn2A, and that p19Arf expression resulted in thymocyte cell death and inhibited the transition from CD4-CD8- (DN) to CD4+CD8+ (DP) stage upstream of the transcriptional factor p53 pathway. The expression of Cdkn2A (the gene encoding p19Arf) in immature thymocytes was directly regulated by PcG complex containing Bmi-1 and M33 through the maintenance of local trimethylated histone H3K27. Our results indicate that this epigenetic regulation critically contributes to the survival of the activated pre-T cells, thereby supporting their proliferation during the DN-DP transition.

Original languageEnglish
Pages (from-to)231-245
Number of pages15
JournalImmunity
Volume28
Issue number2
DOIs
Publication statusPublished - 15-02-2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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