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Science 316 (5822): 295-298

Copyright © 2007 by the American Association for the Advancement of Science

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}

Abstract: 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} (S.R.C.); Jason.Cyster{at} (J.G.C.)

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R. Ohkawa, K. Nakamura, S. Okubo, S. Hosogaya, Y. Ozaki, M. Tozuka, N. Osima, H. Yokota, H. Ikeda, and Y. Yatomi (2008)
Annals of Clinical Biochemistry 45, 356-363
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"Inside-Out" Signaling of Sphingosine-1-Phosphate: Therapeutic Targets.
K. Takabe, S. W. Paugh, S. Milstien, and S. Spiegel (2008)
Pharmacol. Rev. 60, 181-195
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Sphingosine 1-Phosphate Regulates the Egress of IgA Plasmablasts from Peyer's Patches for Intestinal IgA Responses.
M. Gohda, J. Kunisawa, F. Miura, Y. Kagiyama, Y. Kurashima, M. Higuchi, I. Ishikawa, I. Ogahara, and H. Kiyono (2008)
J. Immunol. 180, 5335-5343
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The Enigma of Sphingosine 1-Phosphate Synthesis: A Novel Role for Endothelial Sphingosine Kinases.
J. Igarashi and T. Michel (2008)
Circ. Res. 102, 630-632
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