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

Kathleen B YatesPierre TonnerreGenevieve E MartinUlrike GerdemannRose Al AbosyDawn E ComstockSarah A WeissDavid WolskiDamien C TullyRaymond T ChungTodd M AllenArthur Y KimSarah FidlerJulie FoxJohn FraterGeorg Michael LauerW Nicholas HainingDebattama R Sen
Published in: Nature immunology (2021)
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.
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