TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion

Khan, Omar, Giles, Josephine R, McDonald, Sierra, Manne, Sasikanth, Ngiow, Shin Foong, Patel, Kunal P, Werner, Michael T, Huang, Alexander C, Alexander, Katherine A, Wu, Jennifer E, Attanasio, John, Yan, Patrick, George, Sangeeth M, Bengsch, Bertram, Staupe, Ryan P, Donahue, Greg, Xu, Wei, Amaravadi, Ravi K, Xu, Xiaowei, Karakousis, Giorgos C, Mitchell, Tara C, Schuchter, Lynn M, Kaye, Jonathan, Berger, Shelley L, Wherry, E John (June 2019) TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature, 571 (7764). pp. 211-218. ISSN 0028-0836

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DOI: 10.1038/s41586-019-1325-x

Abstract

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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > quantitative biology organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions bioinformatics > quantitative biology > quantitative genetics > quantitative epistasis bioinformatics > quantitative biology > quantitative genetics organism description > animal > mammal > rodent
CSHL Authors:	Alexander, Katherine
Communities:	CSHL labs > Alexander lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 June 2019
Date Deposited:	16 Jul 2024 15:45
Last Modified:	16 Jul 2024 15:45
PMCID:	PMC6713202
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41614

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