Specific CD8+ T cell immunity in the murine liver
Final Report Abstract
The project focussed on selected aspects of the local, specific CD8 T cell immunity in the liver in the mouse. Priming of CD8 T cell responses to HBV antigens by novel vaccination strategies was investigated, with particular emphasis on eliciting multispecific CD8 T cell responses to subdominant, overlapping, variant or cryptic epitopes discovered on different HBV antigens. The study of the regulation of intra-hepatic specific CDS T cell immunity revealed novel mechanism by which intrahepatic NKT cells and regulator Foxp3 CD4 Treg cells can amplify or suppress intrahepatic CD8 T cell immunity. IL-10, IL- 19/IL-20 and type I interferons were identified as critical mediators of such regulatory effects. The role of PD-L1, HVEM and NKG2D ligands as co receptors in either the local priming of specific CD( T cells by hepatocytes (HC), or the specific local delivery of anti-viral effector functions from CD8 T cells to antigen-bearing HC was elucidated. In vitro studies used initially to identify the molecular interactions involved were complemented by in vivo systems using blocking antibodies, 'knock-out' mice and/or HBV transgenic models. The project addressed (and contributed to solve) questions in basic research on the molecular and cellular factors that allow successful establishment and maintenance of anti-viral CD8 T cell immunity in the liver but also contributed to translational research on therapeutic vaccination strategies against chronic hepatotropic virus infections.
