T cell aggregation induced through CD43: intracellular signals and inhibition by the immunomodulatory drug leflunomide

Abstract: The CD43 coreceptor molecule has been shown to participate in lymphocyte adhesion and activation. Leukocyte homotypic aggregation results from a cascade of intracellular signals de-livered to the cells upon engagement of different cell-surface molecules with their natural ligands. This phenomenon requires an active metabolism, reorganization of the cytoskeleton, and relocaliza-tion of cell-surface molecules. The aim of this study was to identify some of the key members of the signaling cascade leading to T lymphocyte homo-typic aggregation following CD43 engagement. CD43-mediated homotypic aggregation of T lym-phocytes required the participation of Src kinases, phospholipase C-2, protein kinase C, phosphati-dylinositol-3 kinase, as well as extracellular-regu-lated kinase 1/2 and p38. Data shown here suggest that these signaling molecules play a central role in regulating actin cytoskeleton remodeling after CD43 ligation. We also evaluated the ability of immunomodulatory drugs such as leflunomide to block the CD43-mediated homotypic aggregation. Leflunomide blocked the recruitment of targets of the Src family kinases as well as actin polymeriza-tion, diminishing the ability of T lymphocytes to aggregate in response to CD43-specific signals, suggesting that this drug might control the migra-tion and recruitment of lymphoid cells to inflame