| First Author | Khan O | Year | 2019 |
| Journal | Nature | Volume | 571 |
| Issue | 7764 | Pages | 211-218 |
| PubMed ID | 31207603 | Mgi Jnum | J:282948 |
| Mgi Id | MGI:6384279 | Doi | 10.1038/s41586-019-1325-x |
| Citation | Khan O, et al. (2019) TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 571(7764):211-218 |
| abstractText | 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. |
