The Transcription Factor Bhlhe40 Programs Mitochondria! Regulation of Resident CD8+ T Cell Fitness and Functionality
The Transcription Factor Bhlhe40 Programs Mitochondria! Regulation of Resident CD8+ T Cell Fitness and Functionality
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DOI：
10.1016/j.immuni.2019.08.013
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发表时间：
2019-09-17
期刊：
影响因子：
32.4
通讯作者：
Sun, Jie
中科院分区：
文献类型：
--
作者：
Li, Chaofan;Zhu, Bibo;Sun, Jie
组织驻留记忆CD8(+) T （Trm）细胞与肿瘤浸润淋巴细胞（TILs）共享核心驻留基因程序。然而，Trm细胞和TIL发育和功能的转录、代谢和表观遗传调控在很大程度上是不明确的。在这里，我们发现转录因子Bhlhe40是Trm细胞和TIL发育和多功能性所特异性需要的。局部PD-1信号传导抑制TIL Bhlhe40的表达，Bhlhe40对抗pd - l1阻断后TIL的再生至关重要。机制上，Bhlhe40维持了Trm细胞和TIL线粒体！适应性和功能性表观遗传状态。基于这些发现，我们确定了一种表观遗传和代谢方案，可促进与组织驻留和多功能性相关的Trm细胞和TIL基因签名。该方案增强了CD8(+) T细胞的抗肿瘤活性，即使在小鼠肿瘤晚期也具有治疗潜力。我们的研究结果为Trm细胞和TIL功能的局部调控提供了机制见解。
Tissue-resident memory CD8(+) T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondria! fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8(+) T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function.