Selective pharmacological inhibitors reveal differences between Thy-1- and T cell receptor-mediated signal transduction in mouse T lymphocytes.
A compelling body of evidence suggests a role for Thy-1 (CD90), a cell surface glycoprotein of mouse T lymphocytes, in signal transduction resulting in T cell activation. Despite more than 3 decades of investigation, intracellular biochemical events governing the Thy-1 signaling cascade are only vaguely understood. We have employed selective pharmacological inhibitors of signaling molecules to compare downstream elements participating in the Thy-1 signal transduction pathway with those involved in the T cell receptor (TCR)/CD3-associated signaling pathway. Mitogenic anti-Thy-1 or anti-CD3 monoclonal antibody (mAb) were used to cause T cells from C57BL/6 mice to proliferate in the presence or absence of different pharmacological inhibitors. Cyclosporine A, herbimycin A, LY294002, calphostin C and PD98059 all inhibited anti-Thy-1-induced T lymphocyte proliferation, indicating the involvement of calcineurin, protein tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and MEK1 (MAPK kinase 1), respectively, in Thy-1 signaling. Similar results were obtained when T cells were stimulated through the TCR with anti-CD3 monoclonal antibody in the presence or absence of the different inhibitors. Interestingly, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 augmented anti-Thy-1-induced T cell proliferation, whereas anti-CD3-induced proliferative response was partially suppressed by the same inhibitor. The Thy-1 signal transduction pathway, therefore, shares a requirement for calcineurin and several major kinase families with the TCR signaling pathway. However, Thy-1 and TCR-associated signaling pathways are differentially regulated by p38 MAPK.
Haeryfar
S M
SM
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Hoskin
D W
DW
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000502:physiology*; D018800:Thy-1 Antigens / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D011948:Receptors, Antigen, T-Cell; D018800:Thy-1 Antigens; D016572:Cyclosporine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases