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

TitleCell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics.
Publication TypeJournal Article
Year of Publication2010
AuthorsThangada S, Khanna KM, Blaho VA, Oo MLin, Im D-S, Guo C, Lefrancois L, Hla T
JournalJ Exp Med
Volume207
Issue7
Pagination1475-83
Date Published2010 Jul 05
ISSN1540-9538
KeywordsAmino Acid Substitution, Animals, Base Sequence, Cell Membrane, Chemotaxis, Leukocyte, Endocytosis, Fingolimod Hydrochloride, Kinetics, Lymphopenia, Lysophospholipids, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mutant Proteins, Propylene Glycols, Receptors, Lysosphingolipid, Sphingosine, T-Lymphocytes
Abstract

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.

DOI10.1084/jem.20091343
Alternate JournalJ Exp Med
PubMed ID20584883
PubMed Central IDPMC2901064
Grant ListP01 AI056172 / AI / NIAID NIH HHS / United States
F32 CA142117 / CA / NCI NIH HHS / United States
AI056172 / AI / NIAID NIH HHS / United States
R37 HL067330 / HL / NHLBI NIH HHS / United States
R01 HL067330 / HL / NHLBI NIH HHS / United States
R01 AI076457 / AI / NIAID NIH HHS / United States
HL89934 / HL / NHLBI NIH HHS / United States
AI076457 / AI / NIAID NIH HHS / United States
HL67330 / HL / NHLBI NIH HHS / United States
R01 HL089934 / HL / NHLBI NIH HHS / United States
F32CA142117 / CA / NCI NIH HHS / United States

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