Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B.
OBJECTIVE
The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B.


METHODS
A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8(+) T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-gamma and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies.


RESULTS
Intrahepatic HBV-specific CD8(+) cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8(+) cell proliferation and IFN-gamma and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells.


CONCLUSIONS
T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.
Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Paola
P
Fisicaro
Caterina
C
Valdatta
Marco
M
Massari
Elisabetta
E
Loggi
Elisabetta
E
Biasini
Luca
L
Sacchelli
Maria Cristina
MC
Cavallo
Enrico M
EM
Silini
Pietro
P
Andreone
Gabriele
G
Missale
Carlo
C
Ferrari
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation; D005260:Female; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000502:physiology
D000906:Antibodies; D015703:Antigens, CD; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; D007376:Interleukin-2; D053699:Interleukin-7 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma