The expression of PD-1 ligands and their involvement in regulation of T cell functions in acute and chronic woodchuck hepatitis virus infection.
BACKGROUND
The programmed cell death 1 (PD-1)/programmed death-1 ligand 1 (PD-L1) system may play a role in the negative regulation of T cell functions in hepatitis B virus (HBV) infection. Thus, it is important to study its role in the widely used animal model for HBV infection of woodchucks with woodchuck hepatitis virus (WHV).


METHODS
Woodchuck PD-L1 (wPD-L1) and -L2 (wPD-L2) were cloned and characterized. The levels of wPD-L1 expression in primary woodchuck hepatocytes (PWH), peripheral blood mononuclear cells (PBMCs), and liver tissue of naive and WHV-infected woodchucks were examined by real time reverse transcription (RT)-PCR and flow cytometry. Using antibodies against wPD-L1 and -L2, the effect of blocking PD-1/PD-L1/PD-L2 interaction on the proliferation and degranulation of woodchuck PBMCs was examined.


RESULTS
Both wPD-L1 and -L2 showed a high homology to their counterparts of other mammalian species and humans. WPD-L1 expression in PWH and PBMCs of naive animals was low but could be stimulated by Toll-like receptor (TLR) ligands and interferons (IFN). WPD-L1 expression in liver tissue was significantly higher than that measured in PWHs and was slightly elevated during acute and chronic WHV infection. However, wPD-1 and wPD-L1 expression on PBMCs was strongly up-regulated during acute and chronic infection. In vitro blockade with antibodies against wPD-L1 and -L2 partially enhanced proliferation and degranulation of PBMCs from WHV-infected woodchucks.


CONCLUSIONS
Our results demonstrated that wPD-1/wPD-L1 expression in hepatocytes and PBMCs can be induced by different inflammatory stimuli and is up-regulated mainly on PBMCs during WHV infection. A blockade of the woodchuck PD-1/PD-L pathway could partially enhance T cell functions in WHV infection.
Department of Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ejuan
E
Zhang
Xiaoyong
X
Zhang
Jia
J
Liu
Baoju
B
Wang
Yongjun
Y
Tian
Anna D
AD
Kosinska
Zhiyong
Z
Ma
Yang
Y
Xu
Ulf
U
Dittmer
Michael
M
Roggendorf
Dongliang
D
Yang
Mengji
M
Lu
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D003001:Cloning, Molecular; D006509:Hepatitis B / Q000276:immunology* / Q000821:virology; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D008024:Ligands; D008392:Marmota / Q000276:immunology* / Q000821:virology*; D008969:Molecular Sequence Data; D010802:Phylogeny; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D051193:Toll-Like Receptors / Q000378:metabolism
D060890:B7-H1 Antigen; D008024:Ligands; D061027:Programmed Cell Death 1 Ligand 2 Protein; D051193:Toll-Like Receptors; D007372:Interferons