Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, Australia.
Nat Immunol. 2017 Jan;18(1):96-103. doi: 10.1038/ni.3598. Epub 2016 Nov 7.
T lymphocytes and B lymphocytes integrate activating signals to control the size of their proliferative response. Here we report that such control was achieved by timed changes in the production rate of cell-cycle-regulating proto-oncoprotein Myc, with division cessation occurring when Myc levels fell below a critical threshold. The changing pattern of the level of Myc was not affected by cell division, which identified the regulating mechanism as a cell-intrinsic, heritable temporal controller. Overexpression of Myc in stimulated T cells and B cells did not sustain cell proliferation indefinitely, as a separate 'time-to-die' mechanism, also heritable, was programmed after lymphocyte activation and led to eventual cell loss. Together the two competing cell-intrinsic timed fates created the canonical T cell and B cell immune-response pattern of rapid growth followed by loss of most cells. Furthermore, small changes in these timed processes by regulatory signals, or by oncogenic transformation, acted in synergy to greatly enhance cell numbers over time.
T 淋巴细胞和 B 淋巴细胞整合激活信号来控制其增殖反应的大小。在这里,我们报告说,这种控制是通过细胞周期调节原癌蛋白 Myc 的产生率的定时变化来实现的,当 Myc 水平下降到一个关键阈值以下时,细胞分裂就会停止。Myc 水平的变化模式不受细胞分裂的影响,这将调节机制确定为细胞内在的、可遗传的时间控制器。在刺激的 T 细胞和 B 细胞中过表达 Myc 并不能无限期地维持细胞增殖,因为在淋巴细胞激活后,还存在一个独立的、可遗传的“死亡时间”机制,最终导致细胞丢失。这两个相互竞争的细胞内在的定时命运共同创造了典型的 T 细胞和 B 细胞免疫反应模式,即快速生长,然后大多数细胞丢失。此外,通过调节信号或致癌转化,对这些定时过程的微小改变会协同作用,随着时间的推移大大增加细胞数量。