LFA-1 activates focal adhesion kinases FAK1/PYK2 to generate LAT-GRB2-SKAP1 complexes that terminate T-cell conjugate formation

Monika Raab, Yuning Lu, Karsten Kohler, Xin Smith, Klaus Strebhardt and Christopher E. Rudd ()
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Monika Raab: Cell Signaling Section, Tennis Court Road, University of Cambridge
Yuning Lu: Cell Signaling Section, Tennis Court Road, University of Cambridge
Karsten Kohler: Cell Signaling Section, Tennis Court Road, University of Cambridge
Xin Smith: Cell Signaling Section, Tennis Court Road, University of Cambridge
Klaus Strebhardt: School of Medicine, J.W. Goethe-University
Christopher E. Rudd: Cell Signaling Section, Tennis Court Road, University of Cambridge

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Lymphocyte function-associated antigen 1 (LFA-1) affinity and avidity changes have been assumed to mediate adhesion to intercellular adhesion molecule-1 for T-cell conjugation to dendritic cells (DC). Although the T-cell receptor (TCR) and LFA-1 can generate intracellular signals, the immune cell adaptor protein linker for the activation of T cells (LAT) couples the TCR to downstream events. Here, we show that LFA-1 can mediate both adhesion and de-adhesion, dependent on receptor clustering. Although increased affinity mediates adhesion, LFA-1 cross-linking induced the association and activation of the protein-tyrosine kinases FAK1/PYK1 that phosphorylated LAT selectively on a single Y-171 site for the binding to adaptor complex GRB-2-SKAP1. LAT-GRB2-SKAP1 complexes were distinct from canonical LAT-GADs-SLP-76 complexes. LFA-1 cross-linking increased the presence of LAT-GRB2-SKAP1 complexes relative to LAT-GADs-SLP-76 complexes. LFA-1-FAK1 decreased T-cell-dendritic cell (DC) dwell times dependent on LAT-Y171, leading to reduced DO11.10 T cell binding to DCs and proliferation to OVA peptide. Overall, our findings outline a new model for LFA-1 in which the integrin can mediate both adhesion and de-adhesion events dependent on receptor cross-linking.

Date: 2017
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DOI: 10.1038/ncomms16001

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