B cells continuously recirculate between secondary lymphoid organs via the blood and lymph in search of antigen. Upon antigen encounter, activated B cells form germinal centres and differentiate into memory B cells and plasma cells. Thus, effective B cell responses to infectious pathogens and vaccinations result in long-lived immunity and survival of the host. However, aberrant B cell responses are also possible and result in antibody-mediated autoimmune diseases and IgE-mediated allergic diseases. The B cell response therefore must be finely tuned to maximise the quality and quantity of the neutralising antibodies produced by rare antigen-specific cells, and at the same minimise the risk of generating pathogenic autoantibodies. The major goals of the lab are therefore to understand the checks and balances that control the output from the immune response.
To study these rare antigen specific B cells the lab uses knock-in mice engineered to express a B cell receptor directed against a model protein antigen developed by the Brink lab while at the Centenary Institute. This provides the opportunity to mutate the protein to generate a family of antigens capable of activating the same B cells over a wide affinity range. Previous work using this model has shown the importance of B cell receptor signal strength as a quality control in plasma cell differentiation. To track the dynamics of antigen-specific B cells in vivo the lab also uses intravital two-photon microscopy. This work began in the Cyster lab at the University of California, San Francisco and has identified the role of subcapsular sinus macrophages in initiating B cell responses in the lymph node. More recently, the lab has developed a method for optically marking cells expressing a genetically-encoded photoconvertible fluorescent and tracking the fate of the marked cells 24-48 hours later. Ongoing work will use this technique to track key events in the evolution of the germinal centre response.
1. Positive and negative selection in the germinal centre.
2. Memory B cell and plasma cell differentiation.
3. Dormant cancer cells in the endosteal bone niche.