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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Veröffentlicht in:	Nature immunology Jg. 22; H. 8; S. 1020 - 1029
Hauptverfasser:	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.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.08.2021 Nature Publishing Group
Schlagworte:	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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Zusammenfassung:	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.
Bibliographie:	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.
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-021-00979-1