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

Abstract

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 Gi, we show that also the pertussis toxin-insensitive GTPase Gq/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. Gq/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 (AlF4−)-induced adhesion to ICAM-1 requires RhoA and contraction; 3) constitutively active Gq 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 ζ-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 ζ-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.

Matrix Metalloproteinase-1 Produced by Human CXCL12-Stimulated Natural Killer Cells

“…23 In this regard, the production of MMP-1 from CXCL12-stimulated NK cells provide an additional function of the G i -coupled pathway-independent signaling that directly regulates NK-cell invasion into tissues on stimulation with CXCL12, mechanisms of which may regulate T cell invasion as described previously. 41 The CXCL12/CXCR4 pathway was first identified to be functionally important in the homing or immobilization of hematopoietic stem cells. 42 Previous studies showed that CXCL12 stimulates homing of hematopietic cells to the target organs (ie, liver), and this process was enhanced by the production of MMPs in liver.…”

The Chemokine Stromal Cell-Derived Factor-1α Modulates α4β7 Integrin-Mediated Lymphocyte Adhesion to Mucosal Addressin Cell Adhesion Molecule-1 and Fibronectin

“…Studies addressing G␣ i and G␣ 13 involvement in modulation of ␣ 4 ␤ 7 -dependent lymphocyte adhesion using mutant forms of these G proteins will be of key importance to characterize their participation in this process. In addition, it has been recently reported that SDF-1␣ activates G q , which mediates LFA-1 activation during in vivo migration of T cell hybridoma cells (53). A possible activation of G q by SDF-1␣ in lymphocytes could represent an additional candidate mechanism contributing to the increase in ␣ 4 ␤ 7 adhesive activity.…”

Activation of Phosphoinositide 3-Kinases by the CCR4 Ligand Macrophage-Derived Chemokine Is a Dispensable Signal for T Lymphocyte Chemotaxis

“…Currently, all chemokine receptors have been shown to couple to G␣ i , with some chemokine receptors also demonstrating the ability to couple to other G proteins as well, such as G␣ q , G␣ 16 and G␣ 11 (56,57). Although the G i inhibitor, pertussis toxin (PTX), had no effect on basal cell migration, it did completely abrogate CCL22-mediated CEM cell chemotaxis (Fig.…”