title: GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood.
abstract: Lymphocytes egress from lymphoid organs in response to sphingosine-1-phosphate (S1P); minutes later they migrate from blood into tissue against the S1P gradient. The mechanisms facilitating cell movement against the gradient have not been defined. Here, we show that heterotrimeric guanine nucleotide-binding protein-coupled receptor kinase-2 (GRK2) functions in down-regulation of S1P receptor-1 (S1PR1) on blood-exposed lymphocytes. T and B cell movement from blood into lymph nodes is reduced in the absence of GRK2 but is restored in S1P-deficient mice. In the spleen, B cell movement between the blood-rich marginal zone and follicles is disrupted by GRK2 deficiency and by mutation of an S1PR1 desensitization motif. Moreover, delivery of systemic antigen into follicles is impaired. Thus, GRK2-dependent S1PR1 desensitization allows lymphocytes to escape circulatory fluids and migrate into lymphoid tissues.
authors.affiliation: Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Tal I
authors.initials: TI
authors.lastname: Arnon
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Charles
authors.initials: C
authors.lastname: Lo
authors.forename: Trung
authors.initials: T
authors.lastname: Pham
authors.forename: Jinping
authors.initials: J
authors.lastname: An
authors.forename: Shaun
authors.initials: S
authors.lastname: Coughlin
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D001769:Blood; D002465:Cell Movement; D018925:Chemokines / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D015536:Down-Regulation; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
chemical_list: D000936:Antigen-Antibody Complex; D018925:Chemokines; D008024:Ligands; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D013110:Sphingosine