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TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion.
- Source :
-
Nature [Nature] 2019 Jul; Vol. 571 (7764), pp. 211-218. Date of Electronic Publication: 2019 Jun 17. - Publication Year :
- 2019
-
Abstract
- Exhausted CD8 <superscript>+</superscript> T (T <subscript>ex</subscript> ) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T <subscript>eff</subscript> ) or memory (T <subscript>mem</subscript> ) CD8 <superscript>+</superscript> T cells. T <subscript>ex</subscript> cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T <subscript>ex</subscript> cells are a distinct immune subset, with a unique chromatin landscape compared with T <subscript>eff</subscript> and T <subscript>mem</subscript> cells. However, the mechanisms that govern the transcriptional and epigenetic development of T <subscript>ex</subscript> cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T <subscript>ex</subscript> cells in mice. TOX is largely dispensable for the formation of T <subscript>eff</subscript> and T <subscript>mem</subscript> cells, but it is critical for exhaustion: in the absence of TOX, T <subscript>ex</subscript> 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 <subscript>ex</subscript> cells. Robust expression of TOX therefore results in commitment to T <subscript>ex</subscript> cells by translating persistent stimulation into a distinct T <subscript>ex</subscript> cell transcriptional and epigenetic developmental program.
- Subjects :
- Animals
Calcineurin metabolism
Calcium Signaling
Feedback, Physiological
Female
Gene Expression Regulation immunology
Genotype
Immunologic Memory
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
NFATC Transcription Factors metabolism
Tumor Escape
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes pathology
Epistasis, Genetic
Homeodomain Proteins metabolism
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 571
- Issue :
- 7764
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 31207603
- Full Text :
- https://doi.org/10.1038/s41586-019-1325-x