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Cytotoxic T-lymphocytes can detect intracellular antigens which are cut into peptides and presented at the cell surface on MHC class I molecules. The protease which is in charge of fragmenting protein antigens is the proteasome. The proteasome (depicted on the left) is constructed like a cylinder of four stacked rings with seven subunits each. Proteolysis occurs in a proteolytic chamber formed by the two inner rings of b-type subunits. Three of the b-type subunits (called d, MB1, and Z) bear the active site subunits of the proteasome. When a cell is stimulated with the antiviral cytokine interferon-g, three additional proteolytic subunits are strongly induced which take the place of the constitutively expressed active site subunits during proteasome neosynthesis. Moreover, the proteasome regulator PA28a/b is induced through interferon-g. Both, PA28a/b and the exchange of active site subunits changes the cleavage properties of the proteasome and the efficiency of peptide processing for antigen presentation. We are interested in the function of these interferon-g induced changes in proteasome composition and study this both with biochemical techniques and by using a virus model of antigen presentation, the lymphocytic choriomeningitis virus of the mouse.
A second focus of our work is on the functional properties of dendritic cells (DC). DCs act like master switches of the immune response because they are the only cells which are able to activate T cells which have not seen their antigen before. DCs capture antigens in the skin and mucous membranes and carry them into the lymph nodes where the immune response is initiated. We study how viral and bacterial antigens activate DCs with the aim of using DCs as cellular vaccines in immunotherapy against tumors. |
