Effect of the infectious dose and the presence of hepatitis C virus core gene on mouse intrahepatic CD8 T cells.
OBJECTIVE
Chronic hepatitis C viral (HCV) infections often result in ineffective CD8 T-cell responses due to functional exhaustion of HCV-specific T cells. However, how persisting HCV impacts CD8 T-cell effector functions remains largely unknown. The aim of this study is to examine the effect of the infectious dose and the presence of HCV core gene.


METHODS
We compared responses of intrahepatic CD8 T cells during infection of wild-type or HCV core transgenic (Tg) mice with various infectious doses of HCV-NS3-expressing recombinant adenovirus (Ad-HCV-NS3).


RESULTS
Using major histocompatibility complex class I tetramer and intracellular interferon (IFN)-γ staining method to track HCV-NS3-specific CD8 T cells, we found that a significant expansion of HCV-NS3-specific CD8 T cells was restricted to a very narrow dosage range. IFN-γ production by intrahepatic CD8 T cells in HCV core Tg mice was suppressed as compared with wild-type mice. Higher levels of expression of regulatory molecules, Tim-3 and PD-1, by intrahepatic CD8 T cells and PD-L1 by intrahepatic antigen-presenting cells were observed in HCV core Tg mice following Ad-HCV-NS3 infection, and the expression increased dependent on infectious dose. Furthermore, we found a significant inverse correlation between the percentages of IFN-γ-producing cells and expression of regulatory molecules in antigen-specific intrahepatic CD8 T cells.


CONCLUSIONS
High infectious dose and the presence of HCV core gene were strongly involved in ineffective CD8 T-cell responses. We consider that HCV core Tg mouse infected with high infectious dose of Ad-HCV-NS3 is useful as a chronic infection model in the development of immunotherapy for chronic hepatitis C.
Department of Microbiology, Saitama Medical University, Saitama, Japan.
Yutaka
Y
Horiuchi
Akira
A
Takagi
Nobuharu
N
Kobayashi
Osamu
O
Moriya
Toshinori
T
Nagai
Kyoji
K
Moriya
Takeya
T
Tsutsumi
Kazuhiro
K
Koike
Toshitaka
T
Akatsuka
T cell; core; functional exhaustion; hepatitis C; infectious dose