title: Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response.
abstract: The lymph node periphery is an important site for many immunological functions, from pathogen containment to the differentiation of helper T cells, yet the cues that position cells in this region are largely undefined. Here, through the use of a reporter for the signaling lipid S1P (sphingosine 1-phosphate), we found that cells sensed higher concentrations of S1P in the medullary cords than in the T cell zone and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this gradient. Natural killer (NK) cells are located at the periphery of the lymph node, predominantly in the medulla, and we found that expression of SPNS2, expression of the S1P receptor S1PR5 on NK cells, and expression of the chemokine receptor CXCR4 were all required for NK cell localization during homeostasis and rapid production of interferon-γ by NK cells after challenge. Our findings elucidate the spatial cues for NK cell organization and reveal a previously unknown role for S1P in positioning cells within the medulla.
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Victoria
authors.identifier: 0000-0001-9376-1279
authors.initials: V
authors.lastname: Fang
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: V Sai
authors.initials: VS
authors.lastname: Chaluvadi
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Willy D
authors.initials: WD
authors.lastname: Ramos-Perez
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Mendoza
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Baeyens
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Rivera
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Microscopy Core, Office of Collaborative Science, New York University Langone Medical Center, New York, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cammer
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Schwab
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D042783:Endothelial Cells / Q000276:immunology*; D006706:Homeostasis; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology
chemical_list: D027321:Anion Transport Proteins; C514936:CXCR4 protein, mouse; D008246:Lysophospholipids; D019718:Receptors, CXCR4; D049349:Receptors, Lysosphingolipid; C572630:Spns2 protein, mouse; C060506:sphingosine 1-phosphate; D007371:Interferon-gamma; D013110:Sphingosine