BCR-intrinsic regulation of memory B cell responses

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The production of antibodies by B lymphocytes is controlled by signals from the B cell antigen recep-tor (BCR). Following the activation of naïve B cells, primary immune responses are characterised by the production of immunoglobulin M (IgM) antibodies. Secondary responses are dominated by IgG antibodies secreted upon activation of Ig class-switched memory B cells. We recently showed that the antigen receptors of class-switched B cells expressing mIgG- or mIgE-containing BCRs possess a conserved tyrosine-based signalling motif that is not present in mIgM- or mIgD-containing BCRs on naïve cells. This motif, termed immunoglobulin tail tyrosine (ITT), amplifies signals from the mIgG- and mIgE-BCR by recruiting a signalling complex that is organised by the adaptor protein Grb2. One of the central aims of our project is to investigate the role of ITT signalling for secondary antibody responses in the mouse. To this end we have generated two novel knock-in mouse strains possessing tyrosine-to-phenylalanine (Y to F) substitutions in the ITTs of mIgG1 or mIgE. The immunological competence of these mice will be analysed in detail. Furthermore, we will determine the contribution of individual signalling components as well as entire signalling networks for the maintenance and/or activation of Ig class-switched memory B cells. This part will be promoted by two technical advances. First, we will perform a comprehensive determination of the global B cell phosphoproteome by quantitative mass spectrometry. Second, we will establish novel fluorescent biosensors to study signalling events in scarce populations of primary memory B cells. Collectively, genetically engineered mouse mutants in combination with novel tools for signal transduction research will provide a basis towards the elucidation of a molecular signal signature of memory B cells.