Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B.
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.
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Paola
P
Fisicaro
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Valeria
V
Barili
Biochemistry and Molecular Biology Unit, Laboratory of Functional Genomics and Protein Engineering, Department of Life Sciences, University of Parma, Parma, Italy.
Barbara
http://orcid.org/0000-0002-5419-7975
B
Montanini
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Greta
G
Acerbi
Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
Manuela
http://orcid.org/0000-0002-1595-6887
M
Ferracin
Center for Life Nanoscience Laboratory IIT-CNLS, Sapienza University Rome, Italy.
Francesca
F
Guerrieri
Center for Life Nanoscience Laboratory IIT-CNLS, Sapienza University Rome, Italy.
Debora
D
Salerno
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Carolina
C
Boni
Unit of Infectious Diseases, IRCCS-Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy.
Marco
M
Massari
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
M Cristina
MC
Cavallo
1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
Glenda
G
Grossi
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Tiziana
T
Giuberti
1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
Pietro
P
Lampertico
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
Gabriele
G
Missale
Center for Life Nanoscience Laboratory IIT-CNLS, Sapienza University Rome, Italy.|Department of Internal Medicine (DMISM), Sapienza University, Rome, Italy.|Cancer Research Center of Lyon (CRCL)-INSERM U1052, Lyon, France.
Massimo
M
Levrero
Biochemistry and Molecular Biology Unit, Laboratory of Functional Genomics and Protein Engineering, Department of Life Sciences, University of Parma, Parma, Italy.|Biopharmanet-Tec Laboratory, University of Parma, Parma, Italy.
Simone
S
Ottonello
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.|Department of Medicine and Surgery, University of Parma, Parma, Italy.
Carlo
C
Ferrari
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006509:Hepatitis B / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
D000975:Antioxidants; D016207:Cytokines; D017382:Reactive Oxygen Species; D013481:Superoxides