RT Journal Article
SR Electronic
T1 Differential nanoscale organisation of LFA-1 modulates T cell migration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 602326
DO 10.1101/602326
A1 Michael J. Shannon
A1 Judith Pineau
A1 Juliette Griffié
A1 Jesse Aaron
A1 Tamlyn Peel
A1 David J. Williamson
A1 Rose Zamoyska
A1 Andrew P. Cope
A1 Georgina H. Cornish
A1 Dylan M. Owen
YR 2019
UL http://biorxiv.org/content/early/2019/04/11/602326.abstract
AB 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.