Science for Health
We are interested in how signalling from the B cell antigen receptor (BCR) regulates antibody responses.
Production of antibodies by B cells is integral to human immunity. However, many pathogens have found ways to evade the antibody response, making the design of new vaccines a continuous challenge. In addition, it is becoming clear that errors in B cell signalling and trafficking result in a variety of autoimmune diseases and lymphoid malignancies. A better understanding of B cell activation will be necessary to develop more effective vaccines and to selectively eliminate diseased B cells. A key question is how are B cell clones selected from the naïve repertoire to expand in immune responses.
We are focusing on the mechanisms by which binding of antigens to the BCR initiates intracellular signalling and antigen internalization, which are together critical for the response of individual B cell clones and also for the growth of certain B cell tumours. First, we are investigating the structure of the BCR and the changes induced by antigen binding that regulate intracellular signalling. A better knowledge of the structure of the BCR can lead to new ways of targeting B cell activation. Second, we study how BCR signalling and internalisation are organized in living B cells.
When B cells encounter antigen, their form immune synapses, where the B cell cytoskeleton organises the signalling and endocytic pathways. We showed that active generation of cytoskeletal forces by B cells is required for antigen extraction from immune synapses and helps in determining the quality of antigen binding by the BCR. These findings have implications for B cell antigen recognition, antibody affinity maturation and for the development of new high-affinity antibodies for diagnosis or therapy.
To understand how are these process regulated in B cells, we have been developing novel methods to image BCR activation and endocytosis in living B cells using various techniques of fluorescence microscopy, including single molecule imaging, FRET, fluorescence reporters and large-scale imaging. We combine the imaging techniques with structural analysis and genetic and nano-mechanical manipulation of the B cells.
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B cell internalisation of antigens depends on mechanical properties of the antigen presenting substrate. Image of single B cells internalising antigen from soft (top), but not stiff (bottom) membrane substrates. Membrane of the substrate is labelled red, antigen is labelled green and B cell membrane is labelled blue.
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