Huang et al. demonstrated that inducible TOX deletion in established LCMV-specific exhausted T cells (Tex) after chronic infection impaired their durability and differentiation. Sustained TOX expression in established Tex cells regulated proliferation, survival, and long-term differentiation. TOX expression preserved Tex-specific chromatin landscapes and transcriptional programs, and countered cell-extrinsic signals in committed Tex cells, constraining cell fate plasticity. TOX deletion endowed established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and
Author Info: (1) 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. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (2) 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. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (3) 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. (4) 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. (5) 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. (6) 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. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (7) 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. (8) 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. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (9) 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. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.
