Thymocyte proliferation induced by pre-T cell receptor signaling is maintained through polycomb gene product Bmi-1-mediated Cdkn2a repression.
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.
Miyazaki
Masaki
M
Department of Immunology, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. fwnk1228@mb.infoweb.ne.jp
Miyazaki
Kazuko
K
Itoi
Manami
M
Katoh
Yuko
Y
Guo
Yun
Y
Kanno
Rieko
R
Katoh-Fukui
Yuko
Y
Honda
Hiroaki
H
Amagai
Takashi
T
van Lohuizen
Maarten
M
Kawamoto
Hiroshi
H
Kanno
Masamoto
M
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D019942:Genes, p16 / Q000502:physiology*; D056484:Jumonji Domain-Containing Histone Demethylases; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000276:immunology / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D010089:Oxidoreductases, N-Demethylating; D063150:Polycomb Repressive Complex 1