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Journals The Journal of Experimental Medicine Volume 207 Issue 7

The sphingosine 1-phosphate receptor 1 (S1P 1 ) promotes lymphocyte egress from lymphoid organs. Previous work showed that agonist-induced internalization of this G protein–coupled receptor correlates with inhibition of lymphocyte egress and results in lymphopenia. However, it is unclear if S1P 1 internalization is necessary for this effect. We characterize a knockin mouse ( S1p1r S5A/S5A ) in which the C-terminal serine-rich S1P 1 motif, which is important for S1P 1 internalization but dispensable for S1P 1 signaling, is mutated. T cells expressing the mutant S1P 1 showed delayed S1P 1 internalization and defective desensitization after agonist stimulation. Mutant mice exhibited significantly delayed lymphopenia after S1P 1 agonist administration or disruption of the vascular S1P gradient. Adoptive transfer experiments demonstrated that mutant S1P 1 expression in lymphocytes, rather than endothelial cells, facilitated this delay in lymphopenia. Thus, cell-surface residency of S1P 1 on T cells is a primary determinant of lymphocyte egress kinetics in vivo. Footnotes Abbreviations used: ERK extracellular signal-regulated kinase ES embryonic stem GPCR G protein–coupled receptor IBMX 3-isobutyl-1-methylxanthine PECAM platelet/endothelial cell adhesion molecule S1P sphingosine 1-phosphate S1P 1 S1P receptor 1 SDF-1 stromal cell–derived factor–1 SP single positive THI 2-acetyl-4-tetrahydroxybutylimidazole Submitted: 19 June 2009 Accepted: 27 May 2010 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms ). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ ).

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Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics

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  • Publisher Rockefeller Univ Press
  • Copyright © 2010 Thangada et al.
  • ISSN 0022-1007
  • eISSN 1540-9538
  • D.O.I. 10.1084/jem.20091343
  • Publisher site Get PDF  

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