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Differential nanoscale organisation of LFA-1 modulates T cell migration

Michael J. Shannon, Judith Pineau, Juliette Griffié, Jesse Aaron, Tamlyn Peel, View ORCID ProfileDavid J. Williamson, Rose Zamoyska, Andrew P. Cope, Georgina H. Cornish, View ORCID ProfileDylan M. Owen
doi: https://doi.org/10.1101/602326
Michael J. Shannon
1Department of Physics and Randall Centre for Cell and Molecular Biophysics, King’s College London, London, UK
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Judith Pineau
1Department of Physics and Randall Centre for Cell and Molecular Biophysics, King’s College London, London, UK
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Juliette Griffié
1Department of Physics and Randall Centre for Cell and Molecular Biophysics, King’s College London, London, UK
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Jesse Aaron
2Advanced Imaging Center, HHMI Janelia Research Campus, Ashburn, Virginia, US
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Tamlyn Peel
3Centre for Inflammation Biology and Cancer Immunology, King’s College London, London, UK
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David J. Williamson
1Department of Physics and Randall Centre for Cell and Molecular Biophysics, King’s College London, London, UK
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  • ORCID record for David J. Williamson
Rose Zamoyska
4School of Biological Sciences, University of Edinburgh, Edinburgh, UK
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Andrew P. Cope
3Centre for Inflammation Biology and Cancer Immunology, King’s College London, London, UK
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Georgina H. Cornish
3Centre for Inflammation Biology and Cancer Immunology, King’s College London, London, UK
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  • For correspondence: dylan.owen@kcl.ac.uk
Dylan M. Owen
1Department of Physics and Randall Centre for Cell and Molecular Biophysics, King’s College London, London, UK
5Institute of Immunology and Immunotherapy and Department of Mathematics, University of Birmingham, Birmingham, UK
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  • ORCID record for Dylan M. Owen
  • For correspondence: dylan.owen@kcl.ac.uk
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Abstract

Effector T-cells rely on integrins to drive adhesion and migration to facilitate their immune function. Heterodimeric transmembrane integrin LFA-1 (αLβ2) regulates adhesion and migration through linkage of the extracellular matrix with the intracellular actin treadmill machinery. We quantitated the velocity and direction of F-actin flow in migrating T-cells alongside single molecule localisation of transmembrane and intracellular LFA-1. Our results show that retrograde actin flow positively correlated and immobile actin negatively correlated with T-cell velocity. Plasma membrane localised LFA-1 forms unique nano-clustering patterns in the leading edge, compared to the mid-focal zone, in migrating T-cells. Deleting the cytosolic phosphatase PTPN22, a negative regulator of integrin signaling, increased T-cell velocity, and leading-edge cluster co-localisation of pY397 FAK, pY416 Src family kinases and LFA-1. These data suggest that differential nanoclustering patterns of LFA-1 in migrating T-cells can instruct intracellular signalling linked with the actin treadmill. Our data presents a paradigm where T cells modulate the nanoscale organisation of adhesion and signalling molecules to fine tune their migration speed. This has implications for the regulation of immune and inflammatory responses.

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Posted April 11, 2019.
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Differential nanoscale organisation of LFA-1 modulates T cell migration
Michael J. Shannon, Judith Pineau, Juliette Griffié, Jesse Aaron, Tamlyn Peel, David J. Williamson, Rose Zamoyska, Andrew P. Cope, Georgina H. Cornish, Dylan M. Owen
bioRxiv 602326; doi: https://doi.org/10.1101/602326
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Differential nanoscale organisation of LFA-1 modulates T cell migration
Michael J. Shannon, Judith Pineau, Juliette Griffié, Jesse Aaron, Tamlyn Peel, David J. Williamson, Rose Zamoyska, Andrew P. Cope, Georgina H. Cornish, Dylan M. Owen
bioRxiv 602326; doi: https://doi.org/10.1101/602326

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