西湖大学董晨小组研究出对耗竭的CD8⁺ T细胞的三维基因组分析揭示了IRF8在其分化和癌症功能中的关键作用。相关论文于2025年11月18日发表在《自然—免疫学》杂志上。

该研究组展示了三维基因组在T细胞衰竭过程中与基因转录变化相关的广泛变化。

此外，课题组发现干扰素调节因子8（IRF8）是一个重要的转录因子，参与重组与衰竭T细胞分化相关的基因的增强子和启动子之间的空间接近性。IRF8缺乏抑制了衰竭CD8⁺ T细胞的分化及其抗肿瘤功能。从机制上讲，IRF8结合到与衰竭T细胞分化相关的基因上，促进了TAD内染色体环的形成。在环锚区，IRF8招募CTCF形成活跃的染色体结构来调节基因转录。这些结果确定了IRF8依赖性染色质拓扑在耗尽的CD8⁺ T细胞分化过程中的关键作用。

研究人员表示，CD8⁺ T细胞在癌症中被耗尽，伴随着表观基因组的广泛变化。然而，高阶染色质组织是否以及如何参与衰竭CD8⁺ T细胞分化尚不清楚。

附：英文原文

Title: Analysis of the three-dimensional genome of exhausted CD8+ T cells reveals a critical role of IRF8 in their differentiation and functions in cancer

Author: Li, Ruifeng, Wei, Kun, Sun, Qinli, Xie, Bowen, Wei, Peng, Xie, Tian, Guo, Xinyi, Chen, Yongzhen, Pan, Birui, Zhao, Zixuan, Ni, Ling, Dong, Chen

Issue&Volume: 2025-11-18

Abstract: CD8+ T cells are rendered exhausted in cancer, accompanied by extensive changes in the epigenome. However, whether and how higher-order chromatin organization is involved in exhausted CD8+ T cell differentiation is unclear. Here, we show extensive changes in the three-dimensional genome during T cell exhaustion associated with changes in gene transcription. Moreover, we identified interferon regulatory factor 8 (IRF8) as an essential transcription factor involved in reorganization of the spatial proximity between enhancers and promoters of genes associated with exhausted T cell differentiation. IRF8 deficiency inhibited the differentiation of exhausted CD8+ T cells and their antitumor function. Mechanistically, IRF8 bound to genes associated with exhausted T cell differentiation and promoted the formation of intra-TAD chromosomal loops. At the loop anchor regions, IRF8 recruited CTCF to form active chromosomal structures to regulate gene transcription. These results thus identify a critical role of IRF8-dependent chromatin topology during exhausted CD8+ T cell differentiation.

DOI: 10.1038/s41590-025-02330-4

Source: https://www.nature.com/articles/s41590-025-02330-4