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WNK1-dependent osmoregulation in CD4⁺ T cell activation

Biggs O'May, Joshua; (2021) WNK1-dependent osmoregulation in CD4⁺ T cell activation. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

CD4+ T cell activation is critical for the initiation of the adaptive immune response. In particular, through the provision of help to B cells, CD4+ T cells are essential for the generation of high-affinity, class-switched antibodies specific for epitopes on invading pathogens. CD4+ T cells also augment the activation of CD8+ cytotoxic T lymphocytes and modulate the effector function of innate immune cells. These features of the immune response are essential for the clearance of many pathogens and are conditional on the ability of a small population of antigen-specific CD4+ T cells to rapidly expand in response to antigenic challenge. In this study we show that this expansion is strongly dependent on the activity of the WNK1 kinase, and that in the absence of WNK1, CD4+ T cells are unable to support a class-switched antibody response. WNK1 has been extensively studied in the distal nephron of the kidney, where it regulates ion transport, and consequently blood pressure, via the STK39 and OXSR1 kinases and the SLC12A-family of ion co-transporters. Here we show that this osmoregulatory function of WNK1 is required for TCR signalling in CD4+ T cells and the subsequent entry of these cells into G1 phase of the cell cycle. Furthermore, having entered the cell cycle, WNK1-deficient T cells show a reduced rate of DNA replication and activate the ATR-mediated cell cycle checkpoint, resulting in a G2/M blockade. CD4+ T cells carrying mutations in both Oxsr1 and Stk39 phenocopy WNK1-deficient T cells, although the defects in TCR-induced proliferation are less severe. Taken together, these data suggest that WNK1 regulates cell cycle progression via the OXSR1 and STK39 signalling pathways, as well as via another, non-canonical pathway. Importantly, the defective TCR signalling and G1 entry exhibited by WNK1-deficient CD4+ T cells can be rescued by activating the cells in hypotonic medium. These novel findings reveal fundamental roles for WNK1 activity and transmembrane water movement in antigen receptor signalling and cell cycle dynamics.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: WNK1-dependent osmoregulation in CD4⁺ T cell activation
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10133612
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