Details

Autor(en) / Beteiligte

• 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

Titel

TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion

Ist Teil von

• Nature (London), 2019-07, Vol.571 (7764), p.211-218

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Exhausted CD8 T (T ) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T ) or memory (T ) CD8 T cells. T cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T cells are a distinct immune subset, with a unique chromatin landscape compared with T and T cells. However, the mechanisms that govern the transcriptional and epigenetic development of T cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T cells in mice. TOX is largely dispensable for the formation of T and T cells, but it is critical for exhaustion: in the absence of TOX, T 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 T cells. Robust expression of TOX therefore results in commitment to T cells by translating persistent stimulation into a distinct T cell transcriptional and epigenetic developmental program.