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Science 333 (6051): 1898-1903

Copyright © 2011 by the American Association for the Advancement of Science

GRK2-Dependent S1PR1 Desensitization Is Required for Lymphocytes to Overcome Their Attraction to Blood

Tal I. Arnon,1 Ying Xu,1 Charles Lo,1 Trung Pham,1 Jinping An,1 Shaun Coughlin,2 Gerald W. Dorn,3 Jason G. Cyster1,*

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.

1 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
2 Cardiovascular Research Institute, University of California San Francisco, 600 16th Street, San Francisco, CA 94143, USA.
3 Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

* To whom correspondence should be addressed. E-mail: jason.cyster{at}ucsf.edu


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