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Ectopic Tcf1 expression instills a stem-like program in exhausted CD8+ T cells to enhance viral and tumor immunity.
Cellular & Molecular Immunology ( IF 21.8 ) Pub Date : 2020-04-27 , DOI: 10.1038/s41423-020-0436-5
Qiang Shan 1, 2 , Sheng'en Hu 3 , Xia Chen 1, 2 , Derek B Danahy 4, 5 , Vladimir P Badovinac 2, 4, 5 , Chongzhi Zang 3 , Hai-Hui Xue 1, 2, 6
Affiliation  

Exhausted CD8+ T (Tex) cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts. A stem cell-like Tex (Tex-stem) subset can self-renew and differentiate into terminally exhausted (Tex-term) cells. Here, we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models. Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade, leading to enhanced viral and tumor control. Mechanistically, ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells, such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes, including Mx1, Tox2, and Runx3. These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.

中文翻译:

异位 Tcf1 表达在耗尽的 CD8+ T 细胞中注入干细胞样程序,以增强病毒和肿瘤免疫。

由于慢性病毒感染和肿瘤环境中的持续抗原暴露,耗尽的 CD8+ T (Tex) 细胞功能失调。干细胞样 Tex (Tex-stem) 子集可以自我更新并分化成终末衰竭 (Tex-term) 细胞。在这里,我们表明异位 Tcf1 表达有效地促进了慢性病毒感染和临床前肿瘤模型中 Tex 干细胞的产生。Tcf1 过表达减少了共抑制受体的表达并增强了多细胞因子的产生能力,同时保留了对检查点封锁的增强反应,从而增强了病毒和肿瘤的控制。从机制上讲,异位表达的 Tcf1 利用现有和新的染色质可接近位点作为转录增强子或阻遏物,并通过在 Tex 干细胞中强制执行预先存在的表达模式来调节转录组,例如增强对 Blimp1 和 Bim 的抑制以及获得新的下游基因,包括 Mx1、Tox2 和 Runx3。这些发现揭示了异位 Tcf1 表达对 Tex 功能恢复的显着影响,并突出了利用 Tcf1 强制转录程序的治疗潜力。
更新日期:2020-04-27
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