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The role of WNK1 in B cell biology
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Dissertation
The role of WNK1 in B cell biology
2019
Overview
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.
Publisher
ProQuest Dissertations & Theses
Subject
