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

Published version
Peer-reviewed

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Article

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Authors

Raab, M 
Kohler, K 
Smith, X 
Strebhardt, K 

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.

Description

Keywords

Adaptor Proteins, Signal Transducing, Cell Cycle Proteins, Dendritic Cells, Focal Adhesion Kinase 1, Focal Adhesion Kinase 2, GRB2 Adaptor Protein, Humans, Jurkat Cells, Lymphocyte Function-Associated Antigen-1, Membrane Proteins, Microtubule-Associated Proteins, Phosphoproteins, Phosphorylation, T-Lymphocytes

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

8

Publisher

Springer Nature
Sponsorship
Wellcome Trust (092627/Z/10/Z)
This work was supported by Wellcome Trust grant (092627/Z/10/Z).