Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans

Kathleen B Yates; Pierre Tonnerre; Genevieve E Martin; Ulrike Gerdemann; Rose Al Abosy; Dawn E Comstock; Sarah A Weiss; David Wolski; Damien C Tully; Raymond T Chung; Todd M Allen; Arthur Y Kim; Sarah Fidler; Julie Fox; John Frater; Georg M Lauer; W Nicholas Haining; Debattama R Sen

doi:10.1038/s41590-021-00979-1

Epigenetic scars of CD8⁺ T cell exhaustion persist after cure of chronic infection in humans

Nat Immunol. 2021 Aug;22(8):1020-1029. doi: 10.1038/s41590-021-00979-1. Epub 2021 Jul 26.

Authors

Kathleen B Yates^{1

2

3}, Pierre Tonnerre^{4

5}, Genevieve E Martin^{6

7}, Ulrike Gerdemann¹, Rose Al Abosy¹, Dawn E Comstock^{1

8}, Sarah A Weiss^{1

8}, David Wolski⁴, Damien C Tully^{9

10}, Raymond T Chung⁴, Todd M Allen⁹, Arthur Y Kim¹¹, Sarah Fidler^{12

13}, Julie Fox^{14

15}, John Frater^{6

16}, Georg M Lauer⁴, W Nicholas Haining^#^{17

18}, Debattama R Sen^#^{19

20}

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA.
⁵ Inserm U976, Institut de Recherche Saint-Louis, Paris, France.
⁶ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁷ Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia.
⁸ Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
⁹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹¹ Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
¹² Division of Medicine, Wright Fleming Institute, Imperial College, London, UK.
¹³ Imperial College National Institute for Health Research Biomedical Research Centre, London, UK.
¹⁴ Department of Genitourinary Medicine and Infectious Disease, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹⁵ King's College National Institute for Health Research Biomedical Research Centre, London, UK.
¹⁶ Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK.
¹⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
¹⁸ Merck Research Laboratories, Boston, MA, USA. [email protected].
¹⁹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
²⁰ Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. [email protected].

^# Contributed equally.

Abstract

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8⁺ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8⁺ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.

Publication types

Clinical Trial, Phase III
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

2-Naphthylamine / therapeutic use
Anilides / therapeutic use
Antigens, Viral / immunology*
Antiviral Agents / therapeutic use
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / pathology*
Chromatin / metabolism
Cyclopropanes / therapeutic use
Epigenesis, Genetic / genetics
Hepacivirus / drug effects
Hepacivirus / immunology*
Hepatitis C, Chronic / drug therapy
Hepatitis C, Chronic / immunology*
High Mobility Group Proteins / genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Immunologic Memory / immunology*
Lactams, Macrocyclic / therapeutic use
Proline / analogs & derivatives
Proline / therapeutic use
Ribavirin / therapeutic use
Ritonavir / therapeutic use
Sulfonamides / therapeutic use
Uracil / analogs & derivatives
Uracil / therapeutic use
Valine / therapeutic use

Substances

Anilides
Antigens, Viral
Antiviral Agents
Chromatin
Cyclopropanes
HIF1A protein, human
High Mobility Group Proteins
Hypoxia-Inducible Factor 1, alpha Subunit
Lactams, Macrocyclic
Sulfonamides
TOX protein, human
ombitasvir
Ribavirin
Uracil
Proline
2-Naphthylamine
dasabuvir
Valine
Ritonavir
paritaprevir

Abstract

Publication types

MeSH terms

Substances

Grants and funding