Role of pro-apoptotic BH3-only proteins in the B cell immune response

• Antragstellerin: Dr. Silke Faina Fischer
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2008 bis 2013
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 70510436

The aim of this project is to understand the role and regulation of pro-apoptotic BH3-only proteins in the shut-down of the B cell immune response. During the immune response antigen-specific B cells are removed in a process that favours the retention of cells with improved affinity for antigen. As we have shown earlier, the BH3-only protein Bim, an initiator of apoptosis in the Bcl-2-regulated pathway, is essential for apoptosis of germinal centerderived memory B cells and antibody-forming cells. In addition, we have currently identified the BH3-only protein Puma as a critical protein for the death of antigen-specific B cells. The investigation of this notion will here be continued to better understand the function and molecular regulation of these apoptogenic proteins. First, the involvement and function of Puma in the primary B cell immune response will be studied in detail. This will include quantitative measurements of antigen-specific B cells, memory B cells and antibody-forming cells from the animal and analysis of in vitro survival of enriched antigen-specific B cells. Screening of immunoglobulin variable region gene diversification by somatic hypermutation will be performed at the single cell level. Moreover, the secondary B cell immune response will also be analysed by studying memory B cells in mice deficient for Puma or Bim, and their ability to differentiate into antibody-forming cells upon reactivation. The third research stream focusses on the molecular regulation of Puma and Bim in the down-regulation of both the primary and secondary B cell immune response. Taken together, my proposed research intends to provide a detailed understanding of the molecular mechanisms governing the down-regulation of the B cell immune response which ensures homeostasis of the B cell memory compartment.

• DFG-Verfahren: Sachbeihilfen