Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.

Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B / Fisicaro, Paola; Barili, Valeria; Montanini, Barbara; Acerbi, Greta; Ferracin, Manuela; Guerrieri, Francesca; Salerno, Debora; Boni, Carolina; Massari, Marco; Cavallo, M. Cristina; Grossi, Glenda; Giuberti, Tiziana; Lampertico, Pietro; Missale, Gabriele; Levrero, Massimo; Ottonello, Simone; Ferrari, Carlo. - In: NATURE MEDICINE. - ISSN 1078-8956. - 23:3(2017), pp. 327-336. [10.1038/nm.4275]

Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B

FISICARO, Paola;Barili, Valeria;MONTANINI, Barbara;ACERBI, GRETA;MASSARI, MARCO;MISSALE, Gabriele;OTTONELLO, Simone;FERRARI, Carlo
2017

Abstract

Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.
Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B / Fisicaro, Paola; Barili, Valeria; Montanini, Barbara; Acerbi, Greta; Ferracin, Manuela; Guerrieri, Francesca; Salerno, Debora; Boni, Carolina; Massari, Marco; Cavallo, M. Cristina; Grossi, Glenda; Giuberti, Tiziana; Lampertico, Pietro; Missale, Gabriele; Levrero, Massimo; Ottonello, Simone; Ferrari, Carlo. - In: NATURE MEDICINE. - ISSN 1078-8956. - 23:3(2017), pp. 327-336. [10.1038/nm.4275]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2822739.5
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