Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection / Barili V.; Fisicaro P.; Montanini B.; Acerbi G.; Filippi A.; Forleo G.; Romualdi C.; Ferracin M.; Guerrieri F.; Pedrazzi G.; Boni C.; Rossi M.; Vecchi A.; Penna A.; Zecca A.; Mori C.; Orlandini A.; Negri E.; Pesci M.; Massari M.; Missale G.; Levrero M.; Ottonello S.; Ferrari C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - 11:1(2020), pp. 604.1-604.20. [10.1038/s41467-019-14137-7]
Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection
Ferracin M.;
2020
Abstract
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.File | Dimensione | Formato | |
---|---|---|---|
2020_Barili-NatComm.pdf
accesso aperto
Tipo:
Versione (PDF) editoriale
Licenza:
Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione
2.33 MB
Formato
Adobe PDF
|
2.33 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.