| First Author | Huang YJ | Year | 2025 |
| Journal | Sci Immunol | Volume | 10 |
| Issue | 105 | Pages | eado3032 |
| PubMed ID | 40053604 | Mgi Jnum | J:364546 |
| Mgi Id | MGI:8170805 | Doi | 10.1126/sciimmunol.ado3032 |
| Citation | Huang YJ, et al. (2025) Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Sci Immunol 10(105):eado3032 |
| abstractText | 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. |
