Schnyder, T; (2012) Molecular Mechanisms of B Cell Activation. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Our body is under constant attack by pathogens such as viruses or bacteria. The immune system has evolved to efficiently counteract these attacks using an array of cells and soluble proteins. In particular, B cells support the immune system by producing high-affinity antibodies, which target pathogens for destruction by recognition of antigenic structures. B cells furthermore contribute to immunological memory to quickly mount responses to secondary challenges by the same pathogen. In order to produce antibodies, B cells need to get activated in secondary lymphoid organs by a two-step process: First, B cells sense antigen molecules on the surface of antigen-presenting cells using their B cell receptor (BCR), which leads to intracellular signalling and antigen acquisition. B cells then present processed antigen molecules to specific helper T cells. Both BCR ligation and adequate T cell help lead to full B cell activation and the production of antigenspecific antibodies. This thesis investigates the early molecular events of B cell activation. Using a combination of genetics, lipid bilayers and high-resolution microscopy we identify a role for the adaptors Grb2 and Dok-3 alongside the ubiquitin ligase Cbl in antigen gathering by B cells. Moreover, we show recruitment of Grb2, Dok-3 and Cbl to the signalling BCR and establish Grb2 as a central downstream adaptor. We further assess the role of several motor proteins in antigen gathering and find that dynein is recruited to the signalling BCR driving antigen gathering by the movement of antigen-containing BCR microclusters on the underlying microtubule network. Interestingly, recruitment of dynein to BCR microclusters is impaired in B cells lacking Grb2, Dok-3 or Cbl. As the amount of antigen acquired by B cells directly correlates with the extent of T cell help, the data presented significantly contributes to our understanding of the early molecular events underlying B cell activation.

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