Miyazaki Masaki, Miyazaki Kazuko, Itoi Manami, Katoh Yuko, Guo Yun, Kanno Rieko, Katoh-Fukui Yuko, Honda Hiroaki, Amagai Takashi, van Lohuizen Maarten, Kawamoto Hiroshi, Kanno Masamoto
Department of Immunology, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Immunity. 2008 Feb;28(2):231-45. doi: 10.1016/j.immuni.2007.12.013.
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.
胸腺细胞在T细胞受体（TCR）基因重排之前会经历大量增殖，以确保TCR库的多样化。由于活化的细胞更容易受到损伤，因此抑制细胞死亡以及促进细胞周期进程对于细胞的充分生长被认为是很重要的。尽管已经研究了前TCR诱导增殖的分子机制，但在增殖阶段防止细胞死亡的机制仍然未知。在这里，我们表明前TCR信号诱导的活化前T细胞的存活需要多梳蛋白家族（PcG）基因产物Bmi-1介导的对Cdkn2A的抑制，并且p19Arf的表达导致胸腺细胞死亡，并在转录因子p53途径的上游抑制从CD4(-)CD8(-)（双阴性，DN）到CD4(+)CD8(+)（双阳性，DP）阶段的转变。未成熟胸腺细胞中Cdkn2A（编码p19Arf的基因）的表达通过包含Bmi-1和M33的PcG复合物对局部三甲基化组蛋白H3K27的维持而受到直接调控。我们的结果表明，这种表观遗传调控对活化前T细胞的存活至关重要，从而支持它们在DN-DP转变过程中的增殖。
