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 SenPublished 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.
Keyphrases
- dna methylation
- gene expression
- genome wide
- transcription factor
- hepatitis c virus
- oxidative stress
- dna damage
- squamous cell carcinoma
- hiv positive
- antiretroviral therapy
- papillary thyroid
- young adults
- stem cells
- high glucose
- hiv testing
- prognostic factors
- men who have sex with men
- south africa
- diabetic rats
- lymph node metastasis
- platelet rich plasma