TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
By O. Khan, Josephine R. Giles, Sierra J. McDonald, Sasikanth Manne, S. Ngiow, K. P. Patel, Michael T. Werner, Alexander C. Huang, Katherine A Alexander, Jennifer E. Wu and 15 more. Nature, 2019
1,336 citations recorded by the source corpus.
Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program. The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells.
Subfields: Immunology
View Paper: https://www.semanticscholar.org/paper/63c899668c5c6400fb5983ec98c27c8c440e97c5
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In Immunology
Citations in the corpus
- Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “The identification of TOX as a critical TF of T cell exhaustion has sparked interest in finding additional regulators (4, 5).”