Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.
Institute for Immunology, Tsinghua University, Beijing, China.
Cell Rep. 2024 Jun 25;43(6):114301. doi: 10.1016/j.celrep.2024.114301. Epub 2024 May 31.
CD8 T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8 T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.
CD8 T 细胞在肿瘤和慢性感染中会衰竭。在异质性衰竭的 T 细胞中，已经发现祖细胞样（Tpex）细胞亚群对于长期肿瘤或病原体控制很重要，也是免疫治疗的主要应答者。我们使用孤儿核受体 NR4A1 的红色荧光蛋白报告小鼠，该受体最初被认为在 T 细胞功能障碍中至关重要，发现该报告基因在肿瘤和慢性感染中的 Tpex 细胞中高度表达。强制表达 Nr4a1 会促进 Tpex 细胞的积累，而 Nr4a1 缺失后则会改善肿瘤控制，这与效应功能的增加但 CD8 T 细胞的长期维持减少有关。整合染色质免疫沉淀测序（ChIP-seq）和 RNA 测序（RNA-seq）分析发现，NR4A1 结合并促进 Tpex 相关基因的表达，同时抑制终末分化相关基因。因此，本研究确定了 NR4A1 在 Tpex 调节中的关键作用，并为免疫治疗提供了一个有前途的靶点。
