Ion fluxes and water movement in T cell migration
File(s)
Author(s)
de Boer, Leonard Louwrens
Type
Thesis
Abstract
Naïve CD4 T cells constantly circulate and migrate within the lymphatics and bloodstream in search of their cognate antigen, and this recirculation is critical for initiating the adaptive immune response. Previous work showed that T cell migration is dependent on the WNK1 kinase, and that WNK1 regulates migration through the movement of ions via the ion co-transporter SLC12A2. Here, I show that WNK1 pathway-dependent ion and water fluxes are required for T cell migration. The WNK1 pathway controls cell volume, and chemokine stimulation results in a WNK1 pathway-dependent cell swelling, showing that WNK1 controls water movement. I demonstrate that WNK1 pathway proteins and their activity localise to the leading edge of migrating T cells, suggesting that WNK1-regulated ion and water fluxes may be local. Furthermore, I show that local ion and water fluxes generate space at the leading edge, regulating the distance between the plasma membrane and the actin cytoskeleton. This local water-dependent swelling could augment the space required for actin polymerisation by the Brownian ratchet, and thereby increase the rate of protruding actin polymerisation. Indeed, I show that ion and water fluxes control both total F-actin polymerisation and retrograde flow rates. In summary, I describe a chemokine-induced signalling pathway that controls T cell migration through WNK1 by regulating ion and water movement at the leading edge, which in turn facilitates actin polymerisation and hence forward cell movement.
Version
Open Access
Date Issued
2021-06
Date Awarded
2021-11
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Tybulewicz, Victor
Strid, Karin
Sponsor
Imperial College London
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)