The Mechanisms of cross-presentation of a long-lived viral protein

• Antragsteller: Professor Dr. Marcus Groettrup (†)
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2006 bis 2010
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 22319548

Several virus-derived proteins are stable and long-lived in infected cells and nevertheless give rise to immunodominant T cell epitopes of cytotoxic T lymphocytes (CTL). Recently we have addressed this enigma for the nucleoprotein (NP) of the lymphocytic choriomeningitis virus (LCMV) and demonstrated that the NP118 epitope can only be presented on H-2Ld class I molecules as long as the NP is synthesized de novo but can not be sustained from degradation of pre-existing and long-lived, mature NP. In this project we would like to investigate how a very long-lived protein like LCMV-NP can be cross-presented by macrophages and dendritic cells. We have recently shown that for cross-presentation the mature NP protein as well as the activity of HSP90 family chaperones are required for LCMV-NP cross-presentation. We will investigate, at what step in cross-presentation HSP90 activity is required, whether HSP90 and NP interact, and what other chaperones and proteases are involved in the cross-presentation of LCMV-NP. Interestingly, the supernatant of necrotic antigen donor cells contains a heat labile factor that is required for NP cross-presentation. This factor will be purified, characterized, and identified by mass-spectrometry. By UV-based cross-linking of LCMV-NP coated microparticles, we will try to identify new proteins that are involved in LCMV-NP processing after endocytosis by macrophages and dendritic cells.

• DFG-Verfahren: Sachbeihilfen