Stromal Cell-Derived Factor-1-Induced LFA-1 Activation During In Vivo Migration of T Cell Hybridoma Cells Requires Gq/11, RhoA, and Myosin, as well as Gi and Cdc42

• Published in: The Journal of immunology (1950) 2001-04, Vol.166 (7), p.4293-4301
• Main Authors: Soede, Ron D. M, Zeelenberg, Ingrid S, Wijnands, Yvonne M, Kamp, Marga, Roos, Ed
• Format: Article
• Language: English
• Subjects: Animals; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - physiology; Cell Migration Inhibition; Cell Movement - genetics; Cell Movement - immunology; Chemokine CXCL12; Chemokines, CXC - antagonists & inhibitors; Chemokines, CXC - physiology; Dactinomycin - metabolism; Genetic Vectors - chemical synthesis; Genetic Vectors - immunology; GTP-Binding Protein alpha Subunits, Gi-Go - physiology; GTP-Binding Protein alpha Subunits, Gq-G11; GTPase-Activating Proteins - physiology; Heterotrimeric GTP-Binding Proteins - genetics; Heterotrimeric GTP-Binding Proteins - physiology; Hybridomas - cytology; Hybridomas - drug effects; Hybridomas - metabolism; Lymphocyte Function-Associated Antigen-1 - metabolism; Mice; Myosins - physiology; rhoA GTP-Binding Protein - genetics; rhoA GTP-Binding Protein - physiology; Stromal Cells - physiology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.7.4293

Dissemination of T cell hybridomas in mice, a model for in vivo migration of memory T cells and for T lymphoma metastasis, depends on the chemokine stromal cell-derived factor-1 (SDF-1) and the integrin LFA-1 and correlates well with invasion into fibroblast cultures. In addition to the known role of the pertussis toxin-sensitive heterotrimeric GTPase G(i), we show that also the pertussis toxin-insensitive GTPase G(q/11) is required for dissemination and invasion. Furthermore, we show that the small GTPases, Cdc42 and RhoA, are involved, and that invasion is blocked by inhibitors of actinomyosin contraction. G(q/11), RhoA, and contraction are specifically required for LFA-1 activation, since 1) they are essential for LFA-1-dependent migration toward low SDF-1 concentrations through ICAM-1-coated filters, but not for migration toward high SDF-1 levels, which is LFA-1 independent; 2) G protein (AlF(4)(-))-induced adhesion to ICAM-1 requires RhoA and contraction; 3) constitutively active G(q) induces aggregation, mediated by LFA-1. We previously reported that binding of this activated LFA-1 to ICAM-1 triggers a signal, transduced by the zeta-associated protein 70 tyrosine kinase, that activates additional LFA-1 molecules. This amplification of LFA-1 activation is essential for invasion. We show here that zeta-associated protein 70-induced LFA-1 activation requires neither Cdc42 and RhoA nor contraction and is thus quite different from that induced by SDF-1. We conclude that two modes of LFA-1 activation, with distinct underlying mechanisms, are required for the in vivo migration of T cell hybridomas.