CCR7/CCL19 controls expression of EDG-1 in T cells

ArticleinJournal of Biological Chemistry 287(15):11656-64 · February 2012with29 Reads
DOI: 10.1074/jbc.M111.310045 · Source: PubMed
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.
    • "Finally, not only antiapoptotic effects [102] and PI3K-mediated PLA2 activation [103] have been attributed to b-arrestin signaling pathways, but also activation of ERK-dependent protein translation (reviewed in ref. [6]). In turn, CCL19-specific translation of S1P1 is mediated via ERK5-dependent translation of KrüppelKr¨Krüppel-like factor 2 and up-regulation of S1P1 in a HuT78 T cell line and primary T cells [54]. It is becoming more and more appreciated that the chemokine receptor activates ensembles of signaling pathways organized as integrated networks [104, 105] rather than signaling through linear second messenger-dependent cascades . "
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    • "Of these two chemokines, CCL21 may play the more dominant role in recruiting naïve lymphocytes into SLO, while CCL19 may be differentially cytoprotective in sustaining nodal populations of lymphocytes (20–22). Prolonged CCR7-mediated signaling into recruited T cells, leads to intrinsic upregulation of the sphingosine-1 phosphate receptor 1, EDG1 (23), which is involved in the ultimate departure of primed T cell populations from SLO into the peripheral blood circulation (24, 25). "
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