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

Nat Commun. 2017 Jul 12:8:16001. doi: 10.1038/ncomms16001.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • KNSTRN protein, human
  • LAT protein, human
  • Lymphocyte Function-Associated Antigen-1
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Phosphoproteins
  • SLP-76 signal Transducing adaptor proteins
  • Focal Adhesion Kinase 1
  • Focal Adhesion Kinase 2
  • PTK2 protein, human
  • PTK2B protein, human