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 surf ace glycoprotein of mouse T lymphocytes, in signal transduction resulting i n T cell activation. Despite more than 3 decades of investigation, intracel lular biochemical events governing the Thy-1 signaling cascade are only vag uely understood. We have employed selective pharmacological inhibitors of s ignaling 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 mon oclonal antibody (mAb) were used to cause T cells from C578L/6 mice to prol iferate in the presence or absence of different pharmacological inhibitors. Cyclosporine A. herbimycin A, LY294002, calphostin C and PD98059 all inhib ited anti-Thy-1-induced T lymphocyte proliferation, indicating the involvem ent of calcineurin, protein tyrosine kinases, phosphatidylinositol 3-kinase , protein kinase C, and MEK1 (MAPK kinase I), respectively, in Thy-1 signal ing. Similar results were obtained when T cells were stimulated through the TCR with anti-CD3 monoclonal antibody in the presence or absence of the di fferent inhibitors. Interestingly, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 augmented anti-Thy-1-induced T cell proliferatio n, whereas anti-CD3-induced proliferative response was partially suppressed by the same inhibitor. The Thy-1 signal transduction pathway, therefore, s hares a requirement for calcineurin and several major kinase families with the TCR signaling pathway. However, Thy-1 and TCR-associated signaling path ways are differentially regulated by p38 MAPK. (C) 2001 Elsevier Science B. V. All rights reserved.