Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
Cell Rep. 2018 Feb 20;22(8):2107-2117. doi: 10.1016/j.celrep.2018.01.072.
The formation of central CD8 T cell memory in response to infection depends on the transcription factor Tcf1 (Tcf7). Tcf1 is expressed at high levels in naive CD8 T cells but downregulated in most CD8 T cells during effector differentiation. The relevance of Tcf1 downregulation for effector differentiation and the signals controlling Tcf1 expression have not been elucidated. Here, we show that systemic inflammatory signals downregulated Tcf1 in CD8 T cells during dendritic cell vaccination and bacterial infections. The suppressive effect was mediated by the inflammatory cytokine interleukin 12 (IL-12), which acted via STAT4 in CD8 T cells. IL-12-induced Tcf1 downregulation required cell cycling, occurred at the transcriptional level, and was prevented in part by inhibiting DNA methyltransferases. Absence of Tcf1 during T cell priming circumvented the need of systemic inflammation for effector differentiation. We conclude that silencing of Tcf1 by systemic inflammation facilitates effector CD8 T cell differentiation.
针对感染产生的中央 CD8 T 细胞记忆的形成取决于转录因子 Tcf1（Tcf7）。Tcf1 在幼稚 CD8 T 细胞中高水平表达，但在大多数 CD8 T 细胞在效应分化过程中下调。Tcf1 下调对效应分化的相关性以及控制 Tcf1 表达的信号尚未阐明。在这里，我们表明在树突状细胞疫苗接种和细菌感染期间，全身性炎症信号在 CD8 T 细胞中下调 Tcf1。抑制作用是由炎症细胞因子白细胞介素 12（IL-12）介导的，IL-12 通过 CD8 T 细胞中的 STAT4 发挥作用。IL-12 诱导的 Tcf1 下调需要细胞周期，在转录水平发生，并且部分通过抑制 DNA 甲基转移酶来预防。在 T 细胞启动期间缺乏 Tcf1 可以避免系统炎症对效应分化的需要。我们得出结论，全身性炎症通过沉默 Tcf1 促进效应 CD8 T 细胞分化。
