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Inhibition of Tyrosine Kinases Blocks Adhesion-Induced T-Cell Coactivation Without Interfering with T-Cell Adhesion to Endothelial Cell–Surface Ligands

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Abstract

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.

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Author notes

  1. Dawn M. Nowlin

    Present address: High Throughput Discovery Department, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA, 92121

  2. Pina M. Cardarelli

    Present address: Coulter Pharmaceutical, 650 Gateway Blvd., South San Francisco, CA, 94080

  3. Lynn Young

    Present address: RW Johnson Pharmaceutical Research Institute–La Jolla, 3210 Merryfield Row, San Diego, CA, 92121

Authors and Affiliations

  1. Department of Biology, Tanabe Research Laboratories, San Diego, CA

    Dawn M. Nowlin, Pina M. Cardarelli, Lynn Young & Katherine A. Felts

  2. Department of Biology, Tanabe Research Laboratories, 4540 Towne Centre Court, San Diego, CA, 92024

    Jason Mah, Marian Mastrangelo & Ronald R. Cobb

  3. Digital Gene Technologies, La Jolla, CA, 92037

    Katherine A. Felts

  4. Protein Expression and Cell Sciences, Berlex Biosciences, Inc., 15049 San Pablo Avenue, Richmond, CA, 94804

    Ronald R. Cobb

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Nowlin, D.M., Cardarelli, P.M., Young, L. et al. Inhibition of Tyrosine Kinases Blocks Adhesion-Induced T-Cell Coactivation Without Interfering with T-Cell Adhesion to Endothelial Cell–Surface Ligands. Inflammation 26, 31–43 (2002). https://doi.org/10.1023/A:1014421829234

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