TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion

Omar Khan, Josephine R. Giles, Sierra McDonald, Sasikanth Manne, Shin Foong Ngiow, Kunal P. Patel, Michael T. Werner, Alexander C. Huang, Katherine A. Alexander, Jennifer E. Wu, John Attanasio, Patrick Yan, Sangeeth M. George, Bertram Bengsch, Ryan P. Staupe, Greg Donahue, Wei Xu, Ravi K. Amaravadi, Xiaowei Xu, Giorgos C. Karakousis, Tara C. Mitchell, Lynn M. Schuchter, Jonathan Kaye, Shelley L. Berger and E. John Wherry ()
Additional contact information
Omar Khan: University of Pennsylvania
Josephine R. Giles: University of Pennsylvania
Sierra McDonald: University of Pennsylvania
Sasikanth Manne: University of Pennsylvania
Shin Foong Ngiow: University of Pennsylvania
Kunal P. Patel: University of Pennsylvania
Michael T. Werner: University of Pennsylvania
Alexander C. Huang: University of Pennsylvania
Katherine A. Alexander: University of Pennsylvania
Jennifer E. Wu: University of Pennsylvania
John Attanasio: University of Pennsylvania
Patrick Yan: University of Pennsylvania
Sangeeth M. George: University of Pennsylvania
Bertram Bengsch: University Medical Center Freiburg
Ryan P. Staupe: University of Pennsylvania
Greg Donahue: University of Pennsylvania
Wei Xu: University of Pennsylvania
Ravi K. Amaravadi: University of Pennsylvania
Xiaowei Xu: University of Pennsylvania
Giorgos C. Karakousis: University of Pennsylvania
Tara C. Mitchell: University of Pennsylvania
Lynn M. Schuchter: University of Pennsylvania
Jonathan Kaye: Cedars-Sinai Medical Center
Shelley L. Berger: University of Pennsylvania
E. John Wherry: University of Pennsylvania

Nature, 2019, vol. 571, issue 7764, 211-218

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1325-x

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