Human Cytomegalovirus Infection of Human Hepatic Sinusoidal Endothelial Cells Modulates T Cell Recruitment into the Liver

• Applicant: Professor Dr. Tony Bruns
• Subject Area: Gastroenterology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193989736

Hepatic sinusoidal endothelial cells (HSEC) control lymphocyte recruitment into the liver and fulfil important immune regulatory functions. They express non-classical adhesion proteins, bind macromolecules, and act as antigen-presenting cells to T cells. In a model of murine cytomegalovirus (mCMV) HSEC were responsible for mCMV latency and reactivation in the liver. MCMV infection of murine HSEC induces the gene expression of several chemokines and adhesion molecules. Furthermore, it promotes the switch from immunotolerance to a potent effector response in co-cultured allogeneic T cells. Thus, there is evidence to suggest that acute and latent CMV infection of hepatic endothelium will modulate the ability of the liver to recruit and activate lymphocytes thereby providing a mechanism to explain how CMV infection can not only provoke a clinically significant hepatitis but also increase hepatic immune activation in graft rejection.However, no data exist on the influence of human CMV (hCMV) infection on T cell recruitment into the liver. The access to human strains of CMV and the ability to isolate hCMV specific T cells will allow investigating these processes for the first time in human cell systems. In this work, we will compare infected and non-infected HSEC by transcriptomic and proteomic profiling to determine factors that might influence lymphocyte interaction. In a flow-based adhesion assay HSEC from hCMV-infected and non-infected patients will be compared for their ability to recruit lymphocytes from flow, including hCMV-specific CD8+ T cells. The use of antibodies and inhibitors to block candidate adhesion molecules and chemokines will help determining cellular and soluble factors that promote leukocyte recruitment. Furthermore, we will determine whether hCMV-infection modulates the ability of HSEC to activate allogeneic T cells, which is particularly relevant in the context of hCMV infection and graft rejection and may provide innovative therapy options.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. David H. Adams