Fleire, S.; (2007) Recognition of membrane ligands by lymphocytes. Doctoral thesis , University of London.

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Abstract

Recognition of membrane-bound ligands is a fundamental event that determines the fate of lymphocytes during immune responses. Extensive studies have been performed in order to understand the recognition of soluble ligands, however very little is known of the parameters that determine the interaction of membrane-bound ligand/receptors. In my PhD thesis 1 have studied how lymphocytes interact with membrane-bound ligands. I initially characterise how B cells recognise membrane-ligands by expressing CFP-tagged antigens on the surface of target cells. To further dissect this process, I have set-up a system of artificial lipid bilayers that allows a quantitative analysis. Fluorescently labelled antigen molecules of varying affinities are displayed at a range of densities on glass-supported bilayers. The interaction of transgenic B cells with them can then be followed by different microscopy techniques in real time. 1 have described a dynamic cellular response in the early stages of the recognition process in which B cells spread and contract on the antigen bearing membranes to collect the bound molecules in a central cluster to later extract it. This response is triggered by signals delivered through the BCR and is an active process guided by actin polymerisation. The extent of the spreading response is dependent on both the antigen density and its affinity for the BCR and it determines the amount of antigen accumulated. I have also set-up a technique to analyse at the molecular level the differential dynamics of reorganisation of key co-receptor molecules involved in triggering B cell activation. Finally, I extended the bilayers system to characterise the interaction of human NK T cells with a set of specific ligands of different affinities for the T cell receptor (TCR). I have determined the thresholds for the formation of the immunological synapse. In summary, 1 have characterised the early events triggered upon membrane-antigen recognition and elucidated a novel mechanism by which B cells are able to gather antigen and therefore perform their biological function.

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