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Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
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Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
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Journal Article
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
2021
Overview
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
2-Naphthylamine - therapeutic use
/ Antigens
/ Antigens, Viral - immunology
/ Antiviral Agents - therapeutic use
/ Biomedical and Life Sciences
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - pathology
/ Cyclopropanes - therapeutic use
/ Epigenesis, Genetic - genetics
/ 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
/ Lactams, Macrocyclic - therapeutic use
/ Proline - analogs & derivatives
/ Sulfonamides - therapeutic use
