Huang Yinghui J, Ngiow Shin Foong, Baxter Amy E, Manne Sasikanth, Park Simone L, Wu Jennifer E, Khan Omar, Giles Josephine R, Wherry E John
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sci Immunol. 2025 Mar 7;10(105):eado3032. doi: 10.1126/sciimmunol.ado3032.
Although checkpoint blockade temporarily improves exhausted CD8 T (T) cell function, the underlying T epigenetic landscape remains largely unchanged, preventing durable T "reinvigoration" in cancer and chronic infections. The transcription factor TOX initiates T epigenetic programming, yet it remains unclear whether TOX continually preserves T biology after T establishment. Here, we demonstrated that induced TOX ablation in committed T cells resulted in apoptotic-driven loss of T 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 cells. Moreover, TOX removal endows established T cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T cells acts as a durable epigenetic barrier reinforcing the T developmental fate. TOX manipulation even after T establishment could therefore provide therapeutic opportunities to rewire T cells in chronic infections or cancer.
尽管检查点阻断可暂时改善耗竭的CD8 T细胞功能，但潜在的T细胞表观遗传格局在很大程度上仍未改变，这阻碍了癌症和慢性感染中T细胞的持久“重振”。转录因子TOX启动T细胞表观遗传编程，但尚不清楚TOX在T细胞建立后是否持续维持T细胞生物学特性。在这里，我们证明在已分化的T细胞中诱导TOX缺失会导致凋亡驱动的T细胞丢失、抑制性受体表达降低以及终末分化减少。基因表达和表观遗传分析揭示了TOX在维持已分化T细胞的染色质可及性和转录模式方面的关键作用。此外，去除TOX赋予已建立的T细胞更大的命运灵活性，使其能够分化为功能更强的效应样T细胞。因此，已建立的T细胞中持续的TOX表达充当了一种持久的表观遗传屏障，强化了T细胞的发育命运。因此，即使在T细胞建立后对TOX进行操控也可为在慢性感染或癌症中重塑T细胞提供治疗机会。
