TOX的持续表达保护了耗尽的CD8 T细胞的表观遗传命运

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-03-07

Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry

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引用次数: 0

摘要

尽管检查点阻断暂时改善了耗尽的CD8 T （Tex）细胞功能，但潜在的Tex表观遗传景观基本保持不变，阻止了癌症和慢性感染中Tex的持久“复活”。转录因子TOX启动Tex的表观遗传编程，但在Tex建立后，TOX是否继续保留Tex的生物学特性尚不清楚。在这里，我们证明了诱导的TOX消融在承诺的Tex细胞中导致凋亡驱动的Tex细胞损失，抑制受体的表达减少，以及终端分化减少。基因表达和表观遗传分析揭示了TOX在维持染色质可及性和转录模式中的关键作用。此外，去除TOX使已建立的Tex细胞具有更大的命运灵活性，能够分化为功能更强的效应样T细胞。因此，在已建立的特克斯细胞中，连续的TOX表达作为一个持久的表观遗传屏障，加强了特克斯的发育命运。因此，即使在Tex建立之后，对TOX进行操作也可以为慢性感染或癌症中的Tex细胞重新布线提供治疗机会。

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Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate

Although checkpoint blockade temporarily improves exhausted CD8 T (T_ex) cell function, the underlying T_ex epigenetic landscape remains largely unchanged, preventing durable T_ex “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates T_ex epigenetic programming, yet it remains unclear whether TOX continually preserves T_ex biology after T_ex establishment. Here, we demonstrated that induced TOX ablation in committed T_ex cells resulted in apoptotic-driven loss of T_ex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed T_ex cells. Moreover, TOX removal endows established T_ex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T_ex cells acts as a durable epigenetic barrier reinforcing the T_ex developmental fate. TOX manipulation even after T_ex establishment could therefore provide therapeutic opportunities to rewire T_ex cells in chronic infections or cancer.

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.