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Originally published in Science Express on 15 March 2007
Science 13 April 2007:
Vol. 316. no. 5822, pp. 295 - 298
DOI: 10.1126/science.1139221

Reports

Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate

Rajita Pappu,1* Susan R. Schwab,2* Ivo Cornelissen,1 João P. Pereira,2 Jean B. Regard,1 Ying Xu,2 Eric Camerer,1 Yao-Wu Zheng,1 Yong Huang,3 Jason G. Cyster,2{dagger} Shaun R. Coughlin1{dagger}

Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.

1 Cardiovascular Research Institute, University of California, San Francisco, 600 16th Street S472D, San Francisco, CA 94143–2240, USA.
2 Howard Hughes Medical Institute (HHMI) and Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143–0414, USA.
3 Drug Studies Unit, Department of Biopharmaceutical Sciences, University of California, San Francisco, 296 Lawrence Street, South San Francisco, CA 94080, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: Shaun.Coughlin{at}ucsf.edu (S.R.C.); Jason.Cyster{at}ucsf.edu (J.G.C.)

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