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GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood.

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.

Pubmed ID: 21960637

Authors

  • Arnon TI
  • Xu Y
  • Lo C
  • Pham T
  • An J
  • Coughlin S
  • Dorn GW
  • Cyster JG

Journal

Science (New York, N.Y.)

Publication Data

September 30, 2011

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI74847
  • Agency: NIAID NIH HHS, Id: R01 AI074847
  • Agency: NIAID NIH HHS, Id: R01 AI074847-05
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Antigen-Antibody Complex
  • B-Lymphocytes
  • Blood
  • Cell Movement
  • Chemokines
  • Chemotaxis, Leukocyte
  • Down-Regulation
  • G-Protein-Coupled Receptor Kinase 2
  • Ligands
  • Lymph Nodes
  • Lysophospholipids
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Receptors, Lysosphingolipid
  • Signal Transduction
  • Sphingosine
  • Spleen
  • T-Lymphocytes