Developing Granzyme B-secreting B cells as a pharmacotherapeutic tool

• Applicant: Dr. Magdalena Hagn
• Subject Area: Immunology ; Pharmacology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 181112311

Antibody secretion, but not cellular cytotoxicity, is generally considered as the main function of B cells. In contrast to this paradigm, we have recently demonstrated that activation of human B cells by the combined stimulation of the interleukin 21 (IL-21)- and of the B cell receptor (BCR) enables these cells to produce and secrete cytotoxic Granzyme B (GrB). GrB, which can effectively induce apoptosis in target cells, constitutes a major component of the secretory granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). Recent studies from our lab indicate that expression of GrB by B cells might play a significant role in early anti-viral immune response and the control of autoimmunity. IL-21 is produced by activated CD4+ T cells, Th17 and NKT cells. It represents a novel and highly promising cytokine for the treatment of neoplastic and infectious diseases. In this research proposal we will investigate in detail how IL-21 affects processing, regulation and function of GrB in B cells from healthy donors or patients with B cell malignancies, Finally, to establish a reliable model for in depth studies of the molecular and (patho)physiological role of GrB expression in B cells, we intend to identify GrB-secreting B cells in mice. Results obtained from this project will have important implications for our understanding of the role of B cells in immunity. Apart from that they are expected to allow identification of novel treatment modalities for malignancies involving B cells.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Dr. Josef A. Trapani