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Nat Immunol DOI:10.1038/s41590-021-00979-1

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

Publication TypeJournal Article
Year of Publication2021
AuthorsYates, KB, Tonnerre, P, Martin, GE, Gerdemann, U, Abosy, RAl, Comstock, DE, Weiss, SA, Wolski, D, Tully, DC, Chung, RT, Allen, TM, Kim, AY, Fidler, S, Fox, J, Frater, J, Lauer, GM, W Haining, N, Sen, DR
JournalNat Immunol
Date Published2021 Aug

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.


Alternate JournalNat Immunol
PubMed ID34312547
Grant ListT32 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