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

KB Yates, P Tonnerre, GE Martin, U Gerdemann… - Nature …, 2021 - nature.com
KB Yates, P Tonnerre, GE Martin, U Gerdemann, R Al Abosy, DE Comstock, SA Weiss…
Nature immunology, 2021nature.com
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 …
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.
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