title: Setting the clock for recirculating lymphocytes.
abstract: In their search for antigens, lymphocytes continuously shuttle among blood vessels, lymph vessels, and lymphatic tissues. Chemokines mediate entry of lymphocytes into lymphatic tissues, and sphingosine 1-phosphate (S1P) promotes localization of lymphocytes to the vasculature. Both signals are sensed through G protein-coupled receptors (GPCRs). Most GPCRs undergo ligand-dependent homologous receptor desensitization, a process that decreases their signaling output after previous exposure to high ligand concentration. Such desensitization can explain why lymphocytes do not take an intermediate position between two signals but rather oscillate between them. The desensitization of S1P receptor 1 (S1PR1) is mediated by GPCR kinase 2 (GRK2). Deletion of GRK2 in lymphocytes compromises desensitization by high vascular S1P concentrations, thereby reducing responsiveness to the chemokine signal and trapping the cells in the vascular compartment. The desensitization kinetics of S1PR1 allows lymphocytes to dynamically shuttle between vasculature and lymphatic tissue, although the positional information in both compartments is static.
authors: Institute of Science and Technology Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
authors: Alexander
authors: A
authors: Eichner
authors: Michael
authors: M
authors: Sixt
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D018925:Chemokines; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; C060506:sphingosine 1-phosphate; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; D013110:Sphingosine