CCR7 Is Recruited to the Immunological Synapse, Acts as Co-stimulatory Molecule and Drives LFA-1 Clustering for Efficient T Cell Adhesion Through ZAP70

Front Immunol. 2019 Jan 14;9:3115. doi: 10.3389/fimmu.2018.03115. eCollection 2018.

Abstract

The chemokine receptor CCR7 guides T cells and dendritic cells to and within lymph nodes to launch the onset of adaptive immunity. Here, we demonstrate that CCR7 in addition acts as a potent co-stimulatory molecule in T cell activation. We found that antigen recognition and engagement of the TCR results in CCR7 accumulation at the immunological synapse where CCR7 and the TCR co-localize within sub-synaptic vesicles. We demonstrate that CCR7 triggering alone is sufficient to recruit and activate ZAP70, a critical kinase for T cell activation, through Src kinase, whereas TCR CCR7 co-stimulation results in increased and prolonged ZAP70 kinase activity. Finally, we show that ZAP70, acting as adapter molecule, is critical for CCR7-mediated inside-out signaling to integrins, thereby modulating LFA-1 valency regulation to promote cell adhesion, a key step in immunological synapse formation and efficient T cell activation.

Keywords: CCR7; LFA-1; TCR; ZAP70; chemokine receptor; immunological synapse; integrins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • Cell Adhesion / immunology
  • Cell Communication / immunology
  • Fibroblasts
  • HEK293 Cells
  • Healthy Volunteers
  • Humans
  • Hybridomas
  • Immunological Synapses / immunology
  • Immunological Synapses / metabolism*
  • Jurkat Cells
  • Lymphocyte Activation
  • Lymphocyte Function-Associated Antigen-1 / immunology
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • Mice
  • Monocytes
  • Primary Cell Culture
  • Receptors, CCR7 / immunology
  • Receptors, CCR7 / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • ZAP-70 Protein-Tyrosine Kinase / immunology
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*

Substances

  • CCR7 protein, human
  • CD3 Complex
  • CD3 antigen, zeta chain
  • Lymphocyte Function-Associated Antigen-1
  • Receptors, CCR7
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human