Intrahepatic T cell responses to hepatotropic viruses in transgenic mice with inducible viral gene expression in the liver

点击翻译按钮获取中文摘要

The clearance of the acute infection of hepatotropic viruses (HBV, HCV) is CD8+ T cell-dependent. The failure of this anti-viral T cell response leads to chronic virus infection; and the reconstitution of this T cell reactivity is the key objective of therapeutic vaccination. Informative preclinical models are required to develop vaccination strategies that prime CD8+ T cell responses with functional anti-viral activity in the liver. The objective of this application is to achieve the select ble (transient) expression of viral genes in the liver using transgenic mice to mimic viral infection. These mice will be generated by crossing two mouse lines: the first line expresses a tamoxifen-inducible Cre recombinase/human estrogen receptor (hEr) fusion protein selectively in the liver from an approved albumin promoter/a-fetoprotein enhancer control region. The second line carries a 'knock in' into the ubiquitously expressed ROSA26 locus of an antigen cassette which requires a Cre-mediated recombination step for activation. The antigen cassette will be tagged by FRT sites, which facilitates the efficient exchange of antigens in ES cells. Crossing both lines will generate a double transgenic line, in which expression of the viral genes is restricted to the liver and inducible. This system will provide a novel preclinical research tool to study priming, or homing of primed anti-viral CD8+ T cells in the liver that transiently expresses antigens of HBV and HCV. The system can be readily modified to study the influence of cytokines (or their signals) in the establishment of functional CD8+ T cell immunity in the liver.