title: CCR7/CCL19 controls expression of EDG-1 in T cells.
abstract: T lymphocytes circulate between the blood, tissues, and lymph. These T cells carry out immune functions, using the C-C chemokine receptor 7 (CCR7) and its cognate ligands, CCL19 and CCL21, to enter and travel through the lymph nodes. Distinct roles for each ligand in regulating T lymphocyte trafficking have remained elusive. We report that in the human T cell line HuT78 and in primary murine T lymphocytes, signaling from CCR7/CCL19 leads to increased expression and phosphorylation of extracellular signal-regulated kinase 5 (ERK5) within eight hours of stimulation. Within 48-72 h we observed peak levels of endothelial differentiation gene 1 (EDG-1), which mediates the egress of T lymphocytes from lymph nodes. The increased expression of EDG-1 was preceded by up-regulation of its transcription factor, Krüppel-like factor 2 (KLF-2). To determine the cellular effect of disrupting ERK5 signaling from CCR7, we examined the migration of ERK5(flox/flox)/Lck-Cre murine T cells to EDG-1 ligands. While CCL19-stimulated ERK5(flox/flox) naïve T cells showed increased migration to EDG-1 ligands at 48 h, the migration of ERK5(flox/flox)/Lck-Cre T cells remained at a basal level. Accordingly, we define a novel signaling pathway that controls EDG-1 up-regulation following stimulation of T cells by CCR7/CCL19. This is the first report to link the two signaling events that control migration through the lymph nodes: CCR7 mediates entry into the lymph nodes and EDG-1 signaling controls their subsequent exit.
authors.affiliation: Department of Microbiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Shannon
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: McBurney
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Wells
authors.forename: Megan E
authors.initials: ME
authors.lastname: Roth
authors.forename: Psachal A
authors.initials: PA
authors.lastname: Calloway
authors.forename: Charles A
authors.initials: CA
authors.lastname: Bill
authors.forename: Shamima
authors.initials: S
authors.lastname: Islam
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Vines
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D054415:Chemokine CCL19 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054421:Chemokine CCL21 / Q000502:physiology; D002633:Chemotaxis; D003713:Dendritic Cells / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D054400:Receptors, CCR7 / Q000378:metabolism / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology
chemical_list: C515460:CCL19 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D008246:Lysophospholipids; D054400:Receptors, CCR7; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D013110:Sphingosine