PT  - JOURNAL ARTICLE
AU  - Michael J. Shannon
AU  - Judith Pineau
AU  - Juliette Griffié
AU  - Jesse Aaron
AU  - Tamlyn Peel
AU  - David J. Williamson
AU  - Rose Zamoyska
AU  - Andrew P. Cope
AU  - Georgina H. Cornish
AU  - Dylan M. Owen
TI  - Differential nanoscale organisation of LFA-1 modulates T cell migration
AID  - 10.1101/602326
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 602326
4099  - http://biorxiv.org/content/early/2019/04/11/602326.short
4100  - http://biorxiv.org/content/early/2019/04/11/602326.full
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.