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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.

Original publication

DOI

10.1038/s41590-021-00979-1

Type

Journal article

Journal

Nature immunology

Publication Date

08/2021

Volume

22

Pages

1020 - 1029

Addresses

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Keywords

CD8-Positive T-Lymphocytes, Chromatin, Humans, Hepacivirus, Hepatitis C, Chronic, Anilides, Lactams, Macrocyclic, Sulfonamides, 2-Naphthylamine, Cyclopropanes, Uracil, Ritonavir, Valine, Proline, High Mobility Group Proteins, Ribavirin, Antigens, Viral, Antiviral Agents, Immunologic Memory, Epigenesis, Genetic, Hypoxia-Inducible Factor 1, alpha Subunit