Nowosad, CR; (2016) Specialised Architecture and Dynamics of Immune Synapses in B Cell Populations. Doctoral thesis , UCL (University College London).

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Abstract

B cells are specialised lymphocytes that are responsible for the production of antibodies during an immune response. When B cells bind membrane-presented antigen they form an immune synapse, which provides the context for coordinated B cell receptor (BCR) signalling and antigen internalisation, both of which are paramount for full B cell activation. Synapse formation has been well characterised in the largest B cell subset- follicular (FO) B cells, although little is known about how synapse formation is altered in less common B subsets, whose activation supports distinct aspects of the antibody response. Germinal center (GC) B cells develop from follicular B cells after antigen stimulation. They are confined to specialised sites in lymphoid organs, where they undergo somatic hypermutation and affinity improvement of their immunoglobulins. BCR signalling is speculated to be largely inactive in GC B cells, with antigen internalisation, processing and presentation to T cells driving their selection. However, there is limited knowledge of synapse formation, signalling and intracellular antigen trafficking in these cells. Using a newly developed high-content, large-scale fluorescent imaging platform we uncovered subset specific differences in synapse formation and mechanisms of antigen extraction in B cells of different subsets. Immunisation or infection-induced GC B cells showed the most striking difference, forming unique peripheral synapses where antigen was internalised by a distinct pathway independent of antigen movement to the centre of the contact. These cells still relied on proximal BCR signalling, but had defects in the NF-κB pathway, supporting a role for T-dependent selection of high affinity clones. GC cells produced higher tugging forces on the BCR than FO cells and were more effective at affinity discrimination. We conclude that unique biomechanical patterns control stringency of antigen binding in GC B cells, and propose that resultant effects on antigen presentation and availability of T cell help ultimately dictate GC B cell fate. Understanding requirements for the activation of GC B cells has applications in rational vaccine design, as well as for B cell malignancies. Therefore, these results have important implications for the future development of novel immunotherapies.

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