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Title: Signalling mechanisms contributing to integrin activation and immunological synapse formation in B cells
Author: Vehlow, A.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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When a B cell encounters specific membrane-bound antigen, a series of signalling events trigger cytoskeletal rearrangements, integrin activation and cell polarisation. This, in turn, allows for B cell spreading and the formation of the immunological synapse (IS) by segregation of the B cell receptor (BCR) and integrins into domains known as central and peripheral supramolecular activation cluster (cSMAC and pSMAC, respectively). While much is known about the signalling pathways triggered by antigen recognition, evidence linking these pathways to integrin activation and IS formation is lacking. Here, confocal microscopy and biochemical approaches were used to dissect the signalling pathways regulating integrin activation and formation of the B cell IS. The obtained data reveals that membrane-bound antigen recognition by the BCR triggers activation of the integrin leukocyte function-associated antigen 1 (LFA-1) by a signalling mechanism involving tyrosine kinases, the GTP/GDP exchange factors Vavl and Vav2, the small GTPase Rac2 and phosphoinositide-3 kinase (PI3K). By supporting LFA-1 activation, this pathway regulates B cell adhesion and formation of the pSMAC at the IS. Furthermore, Vav1 is revealed as the master regulator of B cell spreading. B cell adhesion mediated by the integrin very late antigen 4 (VLA-4) and its recruitment to the IS also rely on tyrosine kinase and PI3K activity. However, in contrast to LFA-1, Vav and Rac proteins seem to have redundant functions. Finally, engagement of LFA-1 and VLA-4 during the initial stage of membrane- antigen recognition leads to tight B cell adhesion and therefore supports B cell spreading when the amount of antigen is low. This may represent a critical mechanism supporting efficient B cell activation in situations of limited antigen availability.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available