Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics.
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.
Thangada
Shobha
S
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Khanna
Kamal M
KM
Blaho
Victoria A
VA
Oo
Myat Lin
ML
Im
Dong-Soon
DS
Guo
Caiying
C
Lefrancois
Leo
L
Hla
Timothy
T
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D007700:Kinetics; D008231:Lymphopenia / Q000235:genetics / Q000473:pathology; D008246:Lysophospholipids / Q000819:agonists / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
D008246:Lysophospholipids; D050505:Mutant Proteins; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine