title: Cross-talk between TCR and CCR7 signaling sets a temporal threshold for enhanced T lymphocyte migration.
abstract: Lymphocyte homing to, and motility within, lymph nodes is regulated by the chemokine receptor CCR7 and its two ligands CCL19 and CCL21. There, lymphocytes are exposed to a number of extracellular stimuli that influence cellular functions and determine the cell fate. In this study, we assessed the effect of TCR engagement on CCR7-mediated cell migration. We found that long-term TCR triggering of freshly isolated human T cells through CD3/CD28 attenuated CCR7-driven chemotaxis, whereas short-term activation significantly enhanced CCR7-mediated, but not CXCR4-mediated, migration efficiency. Short-term activation most prominently enhanced the migratory response of naive T cells of both CD4 and CD8 subsets. We identified distinct roles for Src family kinases in modulating CCR7-mediated T cell migration. We provide evidence that Fyn, together with Ca(2+)-independent protein kinase C isoforms, kept the migratory response of naive T cells toward CCL21 at a low level. In nonactivated T cells, CCR7 triggering induced a Fyn-dependent phosphorylation of the inhibitory Tyr505 of Lck. Inhibiting Fyn in these nonactivated T cells prevented the negative regulation of Lck and facilitated high CCR7-driven T cell chemotaxis. Moreover, we found that the enhanced migration of short-term activated T cells was accompanied by a synergistic, Src-dependent activation of the adaptor molecule linker for activation of T cells. Collectively, we characterize a cross-talk between the TCR and CCR7 and provide mechanistic evidence that the activation status of T cells controls lymphocyte motility and sets a threshold for their migratory response.
authors: Biotechnology Institute Thurgau, University of Konstanz, CH-8280 Kreuzlingen, Switzerland.
authors: Karin
authors: K
authors: Schaeuble
authors: Mark A
authors: MA
authors: Hauser
authors: Eva
authors: E
authors: Singer
authors: Marcus
authors: M
authors: Groettrup
authors: Daniel F
authors: DF
authors: Legler
mesh_terms: D015153:Blotting, Western; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D020239:Receptor Cross-Talk / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: C515370:CCR7 protein, human; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7