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

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.

SUBMITTER: Yates KB

PROVIDER: S-EPMC8600539 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Epigenetic scars of CD8<sup>+</sup> T cell exhaustion persist after cure of chronic infection in humans.

Yates Kathleen B KB Tonnerre Pierre P Martin Genevieve E GE Gerdemann Ulrike U Al Abosy Rose R Comstock Dawn E DE Weiss Sarah A SA Wolski David D Tully Damien C DC Chung Raymond T RT Allen Todd M TM Kim Arthur Y AY Fidler Sarah S Fox Julie J Frater John J Lauer Georg M GM Haining W Nicholas WN Sen Debattama R DR

Nature immunology 20210726 8

T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8<sup>+</sup> 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 e ...[more]

PMID: 34312547

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Project description:Background and aimsDuring chronic hepatitis C virus (HCV) infection, CD8+ T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of "inhibitory" molecules such as PD-1 (programmed cell death protein 1) and/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes.MethodsThe study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8+ T-cells expressing PD-1/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb.ResultsThere was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8+ T-cells. A predominance of NS31406 epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8+PD-1+Tim-3+ T-cells, P=0.0102. Variability (at least two variants) of NS31406 epitope sequence was associated with increased frequencies of global CD8+PD-1+Tim-3+ T-cells (P=0.0197) and lower frequencies of CD8+PD-1-Tim-3- T-cells (P=0.0079). In contrast, infection with NS31073 dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8+PD-1+Tim-3+ T-cells (P=0.0054).ConclusionsOur results indicate that PD-1/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8+ T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8+ T-cell exhaustion in HCV infection.

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

Publications

Epigenetic scars of CD8<sup>+</sup> 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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Epigenetic scars of CD8&lt;sup&gt;+&lt;/sup&gt; T cell exhaustion persist after cure of chronic infection in humans.

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OmicsDI is part of the ELIXIR infrastructure

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

Epigenetic scars of CD8<sup>+</sup> T cell exhaustion persist after cure of chronic infection in humans.