The Third Signal Cytokine Interleukin 12 Rather Than Immune Checkpoint Inhibitors Contributes to the Functional Restoration of Hepatitis D Virus-Specific T Cells.
BACKGROUND
Hepatitis D virus (HDV) infection affects 15-20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV infection.


METHODS
Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used.


RESULTS
Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8+T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4+and CD8+T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus-specific T cells.


CONCLUSIONS
This investigation of virus-specific T-cell immunity in patients with HDV infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.|German Center for Infection Research, Partner Site Hannover-Braunschweig.
Thomas
T
Schirdewahn
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Jan
J
Grabowski
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Solomon
S
Owusu Sekyere
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Birgit
B
Bremer
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Anika
A
Wranke
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Sebastian
S
Lunemann
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Verena
V
Schlaphoff
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Janina
J
Kirschner
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.|German Center for Infection Research, Partner Site Hannover-Braunschweig.
Svenja
S
Hardtke
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.|German Center for Infection Research, Partner Site Hannover-Braunschweig.
Michael Peter
MP
Manns
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.|German Center for Infection Research, Partner Site Hannover-Braunschweig.
Markus
M
Cornberg
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.|German Center for Infection Research, Partner Site Hannover-Braunschweig.
Heiner
H
Wedemeyer
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School.
Pothakamuri Venkata
PV
Suneetha
D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018959:CD57 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D060908:CTLA-4 Antigen / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology; D005260:Female; D019701:Hepatitis D, Chronic / Q000276:immunology* / Q000821:virology; D003698:Hepatitis Delta Virus / Q000737:chemistry / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism; D014779:Virus Replication; D000098815:T-bet Transcription Factor
D018959:CD57 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12
CD4 T cells; CD57; CD8 T cells; CTLA-4; IL-12; PD-1