title: Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling.
abstract: Sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is critical for lymphocyte egress from lymphoid organs. Lymphocytes encounter low S1P concentrations near exit sites before transmigration, yet S1PR1 signaling is rapidly terminated after exposure to S1P. How lymphocytes maintain S1PR1 signaling in a low S1P environment near egress sites is unknown. Here we identify dynamin 2, an essential component of endocytosis, as a novel regulator of T cell egress. Mice with T cell-specific dynamin 2 deficiency had profound lymphopenia and impaired egress from lymphoid organs. Dynamin 2 deficiency caused impaired egress through regulation of S1PR1 signaling, and transgenic S1PR1 overexpression rescued egress in dynamin 2 knockout mice. In low S1P concentrations, dynamin 2 was essential for S1PR1 internalization, which enabled continuous S1PR1 signaling and promoted egress from both thymus and lymph nodes. In contrast, dynamin 2-deficient cells were only capable of a pulse of S1PR1 signaling, which was insufficient for egress. Our results suggest a possible mechanism by which T lymphocytes positioned at exit portals sense low S1P concentrations, promoting their egress into circulatory fluids.
authors.affiliation: Department of Immunobiology, 2 Department of Cell Biology, 3 Program in Cellular Neuroscience, Neurodegeneration, and Repair, and 4 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Tim
authors.initials: T
authors.lastname: Willinger
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Ferguson
authors.forename: João P
authors.initials: JP
authors.lastname: Pereira
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D034285:Dynamin II / Q000172:deficiency / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008231:Lymphopenia / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019707:Receptors, Chemokine / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D060168:Thymocytes / Q000187:drug effects / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D034285:Dynamin II; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D037181:Lectins, C-Type; D008024:Ligands; D008246:Lysophospholipids; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099192:CD69 Antigens; C579276:Gnai1 protein, mouse; C060506:sphingosine 1-phosphate