Processing of virus antigens and induction of cytotoxic T-cells via the ubiquitin - proteasome pathway
The proteasome is a proteolytic system that provides most of the peptide ligands for MHC call I molecules. When cells encounter IFN-g, the three active site subunits of the proteasome are replaced by the inducible immunosubunits. Our project, we will study the extent, the function and regulation of proteasome subunit replacements during the cytotoxic immune response against lymphocytic choriomeningitis virus (LCMV) in the mouse liver. The formation of ubiquitinated proteins is thought to provide the initiation signal for antigen processing via the proteasome. Consequently, the role of ubiquitination for epitope generation will be studied and the potential of selective proteasome inhibitors for modulation the immune response against LCMV will be tested in vivo.
The presentation of LCMV epitopes will be examined in cell lines overexpressing LMP2/LMP7/MECL-1 and Pa28a/b. The hierarchy of these epitopes will be determined in LCMV infected knock out mice deficient for LMP2, LMP7, MECL-1, PA28ab and PA28g and in mice treated with selective proteasome inhibitors.
After LCMV infection, neosynthesis of long-lived proteins was demonstrated to be a perequisite for antigen presentation. It is our goal to investigate if such long-lived proteins can be processed for cross presentation in dendritic cells (DC). Comparison of endogenous and exogenous pathways of antigen presentation will be carried out in LCMV infections. The project aims to delineate the influence of proteasome immunosubunits, PA28a/b, and ubiquitin conjugation on antigen presentation and further analyse the intracellular cross talk in the antigen processing pathways.
- FB Biologie
|Period:||01.04.2003 – 31.03.2005|