Inhibition of tyrosine kinases blocks adhesion-induced T-cell coactivation without interfering with T-cell adhesion to endothelial cell-surface ligands

Inflammation. 2002 Feb;26(1):31-43. doi: 10.1023/a:1014421829234.


Integrin and cell adhesion molecule-regulated cellular adhesion plays an integral part in the recruitment and activation of lymphocytes. T-cell activation is a dynamic process subject to integrin-dependent and -independent regulation. Stimulation of human peripheral blood T cells by the anti-CD3 monoclonal antibody results in a rapid upregulation of integrin affinity. In conjunction with adhesion to endothelial cell-derived ligands and extracellular matrix proteins, anti-CD3 antibodies have been shown to result in significant increases in IL-2 production and T-cell proliferation. Therefore, at least two signal cascades are activated by ligation of the TCR: One results in a change in affinity of integrins for their ligands, whereas the other activates a signaling cascade that leads to gene induction. We investigated the effects of several tyrosine kinase inhibitors on human peripheral blood T-cell adhesion and adhesion-induced costimulation of IL-2 expression and secretion. These compounds did not inhibit anti-CD3-induced short-term (30 min) or long-term (18 hr) T-cell adhesion to VCAM-1, MAdCAM, or ICAM-1. When T cells were stimulated with anti-CD3 and allowed to adhere to VCAM-1, MAdCAM, or ICAM-1 in the presence of these inhibitors; IL-2 production was significantly reduced. The MEK specific inhibitor, PD98059, did not block T-cell adhesion to the various substrates, but it did block IL-2 synthesis. In addition, the tyrosine kinase inhibitors and PD98059 blocked anti-CD3-mediated stimulation of IL-2 synthesis. These data suggest that the signaling mechanism for anti-CD3-mediated integrin activation is distinct from the signaling pathway that results in adhesion-induced IL-2 synthesis via specific integrins and anti-CD3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • CD3 Complex / immunology
  • CD3 Complex / metabolism
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology*
  • Cell Adhesion Molecules / metabolism
  • Dose-Response Relationship, Drug
  • Endothelium / chemistry
  • Endothelium / cytology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interleukin-2 / biosynthesis
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / physiology*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology
  • Signal Transduction*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology*


  • Antibodies, Monoclonal
  • CD3 Complex
  • Cell Adhesion Molecules
  • Enzyme Inhibitors
  • Interleukin-2
  • Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinase Kinases