TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion

Exhausted CD8 + T (T ex ) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T eff ) or memory (T mem ) CD8 + T cells. T ex cells are important clinical targets of checkpoint...

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Vydáno v:	Nature (London) Ročník 571; číslo 7764; s. 211 - 218
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 11.07.2019 Nature Publishing Group
Témata:	13 38 45 631/250/1619/554/1834 631/250/2152/1566 631/250/2152/1566/2493 631/250/2502/2170 631/250/255/2514 64/60 Animals Antigens Calcineurin Calcineurin - metabolism Calcium Signaling Cancer CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - pathology Chromatin Cloning Epigenetics Epistasis, Genetic Exhaustion Feedback, Physiological Female Gene expression Gene Expression Regulation - immunology Genotype Homeodomain Proteins - metabolism Humanities and Social Sciences Immune checkpoint Immunologic Memory Immunological memory Immunotherapy Infections Lymphocytes Lymphocytes T Male Memory cells Mice Mice, Inbred BALB C Mice, Inbred C57BL multidisciplinary NF-AT protein NFATC Transcription Factors - metabolism Receptor mechanisms Receptors Science Science (multidisciplinary) T cell receptors Transcription factors Transcription, Genetic Tumor Escape
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	Exhausted CD8 + T (T ex ) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T eff ) or memory (T mem ) CD8 + T cells. T ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T ex cells are a distinct immune subset, with a unique chromatin landscape compared with T eff and T mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T ex cells in mice. TOX is largely dispensable for the formation of T eff and T mem cells, but it is critical for exhaustion: in the absence of TOX, T ex 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 ex cells. Robust expression of TOX therefore results in commitment to T ex cells by translating persistent stimulation into a distinct T ex cell transcriptional and epigenetic developmental program. The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Lead Contact: E. John Wherry O.K. and E.J.W. conceived the project, designed experiments and wrote the manuscript. O.K. performed the majority of the experiments described herein and performed the in vitro, in vivo, and bioinformatics analysis. J.R.G. wrote the script to perform PSEA and, with S.M., performed pre-processing of RNA and ATAC-seq data. S.M. performed co-IP experiments for Western blot. S.F.N and K.P.P contributed to in vivo tumor and influenza experiments. M.T.W. performed IP experiments for mass spectrometry. A.C.H., P.Y., and S.M.G. acquired and stained human PBMC and TIL samples. J.E.W., R.P.S., and J.R.G. provided critical edits to the manuscript. All authors reviewed the manuscript. Contributions
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-019-1325-x