Title | Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Thangada S, Khanna KM, Blaho VA, Oo MLin, Im D-S, Guo C, Lefrancois L, Hla T |
Journal | J Exp Med |
Volume | 207 |
Issue | 7 |
Pagination | 1475-83 |
Date Published | 2010 Jul 05 |
ISSN | 1540-9538 |
Keywords | Amino 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. |
DOI | 10.1084/jem.20091343 |
Alternate Journal | J Exp Med |
PubMed ID | 20584883 |
PubMed Central ID | PMC2901064 |
Grant List | P01 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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