Epigenetic scars of CD8 T cell exhaustion persist after cure of chronic infection in humans.
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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. |
Year of Publication | 2021
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Journal | Nat Immunol
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Volume | 22
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Issue | 8
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Pages | 1020-1029
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Date Published | 2021 Aug
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ISSN | 1529-2916
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DOI | 10.1038/s41590-021-00979-1
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PubMed ID | 34312547
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Grant list | T32 GM007753 / GM / NIGMS NIH HHS / United States
U19 AI086230 / Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)
R01 AI136715 / AI / NIAID NIH HHS / United States
T32 CA207021 / CA / NCI NIH HHS / United States
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