Inhibition of tyrosine kinases blocks adhesion-induced T-cell coactivation without interfering with T-cell adhesion to endothelial cell-surface ligands.
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.
Nowlin
Dawn M
DM
Department of Biology, Tanabe Research Laboratories, San Diego, CA 92024, USA.
Cardarelli
Pina M
PM
Young
Lynn
L
Mah
Jason
J
Felts
Katherine A
KA
Mastrangelo
Marian
M
Cobb
Ronald R
RR
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000737:chemistry / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011505:Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases