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The Role of WNK1 in B Cell Biology

Hayward, Darryl Antony; (2019) The Role of WNK1 in B Cell Biology. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

WNK1 is a kinase that has been implicated in ion homeostasis in cells through the activation of the kinases OXSR1 and STK39, which in turn phosphorylate the NKCC- and KCC-families of ion cotransporters leading to their activation and inhibition respectively. Mutations in the human WNK1 gene that cause overexpression of WNK1 result in pseudohypoaldosteronism type II, a condition where individuals present with hypertension and high concentrations of potassium in their blood. WNK1 has been implicated in migration and cell division in cancer cells. Work in CD4+ T cells has shown that WNK1 is a negative regulator of adhesion and a positive regulator of migration, but the function of WNK1 in other immune cells remains unknown. The work presented in this thesis describes the function of WNK1 in B cells. I have used inducible deletion of WNK1 in both naïve and activated B cells, as well as an inhibitor of WNK1, to assess the role of WNK1 in mature B cell biology. I have shown that WNK1 is a crucial kinase for several aspects of B cell biology in mice, since loss of Wnk1 expression caused dysregulation of B cell survival, adhesion, migration and development. WNK1 is required in B cells during an immune response as it positively regulates proliferation after activation. Furthermore, WNK1- deficient B cells display defects in antigen presentation to CD4+ T cells as well as defective responses to stimulation with CD40L, highlighting a role for WNK1 in the regulation of crosstalk between B and CD4+ T cells. WNK1-deficient B cells are not able to mount a T-dependent antibody response nor differentiate into germinal centre B cells. Taken together this work indicates that WNK1 is absolutely required for multiple aspects of B cell function.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Role of WNK1 in B Cell Biology
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
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: https://discovery.ucl.ac.uk/id/eprint/10081500
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