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; E John Wherry

doi:10.1038/s41586-019-1325-x

TOX transcriptionally and epigenetically programs CD8⁺ T cell exhaustion

Nature. 2019 Jul;571(7764):211-218. doi: 10.1038/s41586-019-1325-x. Epub 2019 Jun 17.

Authors

Omar Khan^{1

2

3

4}, Josephine R Giles^{1

2

3}, Sierra McDonald^{5

6

7}, Sasikanth Manne^{1

2}, Shin Foong Ngiow^{1

2

3}, Kunal P Patel^{1

2

8}, Michael T Werner^{5

7}, Alexander C Huang^{2

3

8}, Katherine A Alexander^{5

6

7}, Jennifer E Wu^{1

2

3}, John Attanasio^{1

2}, Patrick Yan^{1

2}, Sangeeth M George^{1

2}, Bertram Bengsch^{9

10}, Ryan P Staupe^{1

2}, Greg Donahue^{5

6

7}, Wei Xu¹¹, Ravi K Amaravadi^{8

11}, Xiaowei Xu^{11

12}, Giorgos C Karakousis^{11

13}, Tara C Mitchell^{8

11}, Lynn M Schuchter^{8

11}, Jonathan Kaye¹⁴, Shelley L Berger^{5

6

7}, E John Wherry^{15

16

17}

Affiliations

¹ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Arsenal Biosciences, South San Francisco, CA, USA.
⁵ Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Department of Medicine II: Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany.
¹⁰ BIOSS Centre for Biological Signaling Studies, Freiburg, Germany.
¹¹ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁵ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
¹⁶ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
¹⁷ Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.

Abstract

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.

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology*
Calcineurin / metabolism
Calcium Signaling
Epistasis, Genetic*
Feedback, Physiological
Female
Gene Expression Regulation / immunology
Genotype
Homeodomain Proteins / metabolism*
Immunologic Memory
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
NFATC Transcription Factors / metabolism
Transcription, Genetic*
Tumor Escape

Substances

Homeodomain Proteins
NFATC Transcription Factors
Nfatc1 protein, mouse
Rhox8 protein, mouse
Calcineurin

Abstract

MeSH terms

Substances

Grants and funding