The role of innate receptors in dendritic cell and B lymphocyte activation
The main focus of this project is to understand the role of microbial products and their receptor, such as Toll like receptors (TLRs), in the activation dendritic cells (DC) and B lymphocytes. The first aim is to determine how the nature, duration and combination of signals emanating from TLRs, cytokine receptors control and CD40 control specific DC maturation programs, such as migration, antigen presentation, and cytokine production, and how these ultimately impact on the capacity of DCs to elicit T lymphocyte responses. The second aim is to understand the role of microbial products and TLRs in human B cell activation with the aim of enhancing B cell and antibody responses. The third aim is to develop and validate a method to measure the frequency of human antigen-specific memory B cells. This method, which is based on B cell stimulation with TLR agonists, will be used to measure the frequency of memory B cells producing antibodies of different specificity and function, for instance those capable of neutralizing viral infection and those that lack such activity. The data obtained will be used to develop a mathematical model of serological memory and to determine what is the fraction of the antibody response which is useful for host protection. These studies are expected to provide relevant information for the design of adjuvants capable of selectively enhancing T or B cell responses. Furthermore the improved method of polyclonal B cell activation will be instrumental to study the human memory B cell repertoire in physiological and pathological conditions. These studies, combined with the possibility of isolating human monoclonal antibodies, will ultimately impact on both active and passive vaccination.