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

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...

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Vydáno v:	Nature immunology Ročník 22; číslo 8; s. 1020 - 1029
Hlavní autoři:	Yates, Kathleen B., Tonnerre, Pierre, Martin, Genevieve E., Gerdemann, Ulrike, Al Abosy, Rose, Comstock, Dawn E., Weiss, Sarah A., Wolski, David, Tully, Damien C., Chung, Raymond T., Allen, Todd M., Kim, Arthur Y., Fidler, Sarah, Fox, Julie, Frater, John, Lauer, Georg M., Haining, W. Nicholas, Sen, Debattama R.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.08.2021 Nature Publishing Group
Témata:	2-Naphthylamine - therapeutic use 631/1647/2210/2211 631/250/255/1901 631/250/255/234/2513/1551 692/420/2780/2152/1566/2493 Anilides - therapeutic use Antigens Antigens, Viral - immunology Antiviral Agents - therapeutic use Biomedical and Life Sciences Biomedicine CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - pathology Chromatin Chromatin - metabolism Chronic infection Cyclopropanes - therapeutic use Enhancers Epigenesis, Genetic - genetics Epigenetics Hepacivirus - drug effects Hepacivirus - immunology Hepatitis C, Chronic - drug therapy Hepatitis C, Chronic - immunology High Mobility Group Proteins - genetics HIV Human immunodeficiency virus Humans Hypoxia-Inducible Factor 1, alpha Subunit - genetics Immunologic Memory - immunology Immunology Infections Infectious Diseases Inflammation Lactams, Macrocyclic - therapeutic use Lymphocytes Lymphocytes T Plasticity Proline - analogs & derivatives Proline - therapeutic use Ribavirin - therapeutic use Ritonavir - therapeutic use Sulfonamides - therapeutic use Uracil - analogs & derivatives Uracil - therapeutic use Valine - therapeutic use
ISSN:	1529-2908, 1529-2916, 1529-2916
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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. The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8 + T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen.
AbstractList	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. 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. The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8 + T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen. 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.The degree of plasticity in the epigenetic landscape of exhausted T cells has been unclear. Sen and colleagues find that exhausted CD8+ T cells demonstrate a stable core epigenetic exhaustion signature that persists independent of inflammation or viral antigen. 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 resolution of 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, therefore, is 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. 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.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.
Author	Weiss, Sarah A. Chung, Raymond T. Gerdemann, Ulrike Fidler, Sarah Comstock, Dawn E. Lauer, Georg M. Frater, John Yates, Kathleen B. Wolski, David Allen, Todd M. Martin, Genevieve E. Tully, Damien C. Haining, W. Nicholas Tonnerre, Pierre Al Abosy, Rose Sen, Debattama R. Kim, Arthur Y. Fox, Julie
AuthorAffiliation	5. Inserm U976, Institut de Recherche Saint-Louis, Paris, France 2. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA 4. Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA 1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 11. Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA 16. Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK 9. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA 3. Broad Institute of MIT and Harvard, Cambridge, MA, USA 17. Merck Research Laboratories, Boston, MA, USA 7. Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia 14. Department of Genitourinary Medicine and Infectious Disease, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom 15. King’s College National Institute for Health Research Biomedical Researc
AuthorAffiliation_xml	– name: 2. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA – name: 15. King’s College National Institute for Health Research Biomedical Research Centre, London, United Kingdom – name: 5. Inserm U976, Institut de Recherche Saint-Louis, Paris, France – name: 9. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA – name: 14. Department of Genitourinary Medicine and Infectious Disease, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom – name: 12. Division of Medicine, Wright Fleming Institute, Imperial College, London, United Kingdom – name: 6. Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK – name: 16. Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK – name: 1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA – name: 3. Broad Institute of MIT and Harvard, Cambridge, MA, USA – name: 13. Imperial College National Institute for Health Research Biomedical Research Centre, London, United Kingdom – name: 8. Division of Medical Sciences, Harvard Medical School, Boston, MA – name: 10. Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK – name: 11. Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA – name: 4. Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA – name: 7. Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia – name: 17. Merck Research Laboratories, Boston, MA, USA
Author_xml	– sequence: 1 givenname: Kathleen B. orcidid: 0000-0002-7383-5573 surname: Yates fullname: Yates, Kathleen B. organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Broad Institute of MIT and Harvard – sequence: 2 givenname: Pierre orcidid: 0000-0002-1719-9736 surname: Tonnerre fullname: Tonnerre, Pierre organization: Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Inserm U976, Institut de Recherche Saint-Louis – sequence: 3 givenname: Genevieve E. orcidid: 0000-0001-5142-7440 surname: Martin fullname: Martin, Genevieve E. organization: Nuffield Department of Medicine, University of Oxford, Department of Infectious Diseases, Central Clinical School, Monash University – sequence: 4 givenname: Ulrike surname: Gerdemann fullname: Gerdemann, Ulrike organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute – sequence: 5 givenname: Rose orcidid: 0000-0001-5400-1306 surname: Al Abosy fullname: Al Abosy, Rose organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute – sequence: 6 givenname: Dawn E. orcidid: 0000-0002-3718-8372 surname: Comstock fullname: Comstock, Dawn E. organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute, Division of Medical Sciences, Harvard Medical School – sequence: 7 givenname: Sarah A. orcidid: 0000-0002-4155-0346 surname: Weiss fullname: Weiss, Sarah A. organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute, Division of Medical Sciences, Harvard Medical School – sequence: 8 givenname: David surname: Wolski fullname: Wolski, David organization: Division of Gastroenterology, Liver Center, Massachusetts General Hospital – sequence: 9 givenname: Damien C. orcidid: 0000-0002-7620-9340 surname: Tully fullname: Tully, Damien C. organization: Ragon Institute of MGH, MIT and Harvard, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine – sequence: 10 givenname: Raymond T. surname: Chung fullname: Chung, Raymond T. organization: Division of Gastroenterology, Liver Center, Massachusetts General Hospital – sequence: 11 givenname: Todd M. orcidid: 0000-0002-6609-1318 surname: Allen fullname: Allen, Todd M. organization: Ragon Institute of MGH, MIT and Harvard – sequence: 12 givenname: Arthur Y. surname: Kim fullname: Kim, Arthur Y. organization: Division of Infectious Diseases, Massachusetts General Hospital – sequence: 13 givenname: Sarah surname: Fidler fullname: Fidler, Sarah organization: Division of Medicine, Wright Fleming Institute, Imperial College, Imperial College National Institute for Health Research Biomedical Research Centre – sequence: 14 givenname: Julie surname: Fox fullname: Fox, Julie organization: Department of Genitourinary Medicine and Infectious Disease, Guy’s and St Thomas’ NHS Foundation Trust, King’s College National Institute for Health Research Biomedical Research Centre – sequence: 15 givenname: John orcidid: 0000-0001-7163-7277 surname: Frater fullname: Frater, John organization: Nuffield Department of Medicine, University of Oxford, Oxford National Institute for Health Research Biomedical Research Centre – sequence: 16 givenname: Georg M. orcidid: 0000-0002-9792-4271 surname: Lauer fullname: Lauer, Georg M. organization: Division of Gastroenterology, Liver Center, Massachusetts General Hospital – sequence: 17 givenname: W. Nicholas orcidid: 0000-0001-7871-3762 surname: Haining fullname: Haining, W. Nicholas email: nick.haining@merck.com organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute, Merck Research Laboratories – sequence: 18 givenname: Debattama R. orcidid: 0000-0002-0947-8284 surname: Sen fullname: Sen, Debattama R. email: dsen@mgh.harvard.edu organization: Department of Pediatric Oncology, Dana–Farber Cancer Institute, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/34312547$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. The Author(s), under exclusive licence to Springer Nature America, Inc. 2021.
Copyright_xml	– notice: The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 – notice: 2021. The Author(s), under exclusive licence to Springer Nature America, Inc. – notice: The Author(s), under exclusive licence to Springer Nature America, Inc. 2021.
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DOI	10.1038/s41590-021-00979-1
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally. Author Contributions D.R.S. and W.N.H. conceived of the study and designed the experiments. D.R.S., K.B.Y., G.E.M., U.G., R.A., D.E.C., S.A.W. performed experiments and/or data analysis. P.T., D.W., D.C.T., R.T.C., T.A., A.Y.K., G.M.L. contributed to the HCV clinical trial design, patient recruitment, sample processing, viral sequencing studies and/or transcriptional analysis. G.E.M., S.F., J. Frater., J. Fox contributed to the HIV clinical trial design, patient recruitment, and/or sample processing. D.R.S. and W.N.H. wrote the manuscript; all authors reviewed and edited the manuscript.
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Snippet	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... 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... 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...
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Title	Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
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