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Regulation of B cell responses by Rho GTPases

Burbage, MM; (2015) Regulation of B cell responses by Rho GTPases. Doctoral thesis , UCL (University College London). Green open access

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Abstract

B cells provide a critical line of defence from pathogenic infections through the production of highly specific antibodies. B cells are characterised by the expression of a specific receptor, namely the B cell receptor (BCR), which can be activated by binding to a cognate antigen. Several studies have brought evidence that in vivo, B cells encounter mostly antigen presented on the surface of specific cells, such as macrophages or follicular dendritic cells. Recognition of membrane bound antigen by B cells is associated with radical morphological changes as B cell rapidly spread then contract on the antigen containing surface. These events rely on important remodelling of the actin cytoskeleton. The actin cytoskeleton is also involved in regulation of signalling in B cells at steady state. Furthermore, mutations in different proteins involved in cytoskeleton regulation, such as WASp or DOCK8 have been associated with immunodeficiencies in human patients. Despite its established importance in B cell responses, the precise regulation of the actin cytoskeleton in B cells is still poorly understood. To address this question, I set out to analyse the function of a family of small GTPases related to Cdc42 in B cells. In particular, I focused on Cdc42 itself and on a closely related molecule named TC10. Both these proteins can interact with DOCK8 and are highly expressed in B cells. After generating transgenic mouse lines deficient in either of these Rho GTPases, I performed a comparative characterisation of the two strains by analysing B cell development as well as antibody responses to T dependent antigen. Although deletion of either Cdc42 or TC10 caused defects in antibody responses, the effect of Cdc42 inactivation was of striking magnitude. Then, I further characterised the role of Cdc42 in B cell physiology. I found that complete deletion of Cdc42 in B cells was associated with very strong defects in B cell responses, as the mice were virtually unable to form antibodies following viral infection. This severe immune deficiency was caused by multiple and profound B cell abnormalities which will be discussed here. Altogether, our results highlight the central role of Cdc42 in B cell responses. In view of the importance of Cdc42 in B cell physiology, I sought to characterise the molecules involved in its regulation. Specifically, I performed a preliminary study on intersectin 2, a G-nucleotide exchange factor for Cdc42. Preliminary results suggest that intersectin 2 deficient B cells have are defective in reorganising their actin cytoskeleton after activation, and that antibody production after immunisation is compromised in ITSN2 deficient animals.

Type: Thesis (Doctoral)
Title: Regulation of B cell responses by Rho GTPases
Event: UCL (University College London )
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1473409
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