title: ATP gradients inhibit the migratory capacity of specific human dendritic cell types: implications for P2Y11 receptor signaling.
abstract: Dendritic cells (DCs) are specialized antigen-presenting cells residing in tissues, from which they take up antigen. Activated DCs migrate through chemokine gradients from sites of inflammation to lymph nodes to stimulate T cells. At sites of inflammation, nucleotides, such as adenosine triphosphate (ATP), are released by activated or dying cells and can function as signaling molecules through P2 receptors (P2Rs). We investigated P2R expression in different DC populations and the effect of nucleotides on chemokine-directed migration. Exposure of monocyte-derived DCs (MoDCs) and CD1a+ dermal DCs to gradients of ATP inhibited their migratory capacity in a dose-dependent manner. Studies using P2R agonists and antagonists implicated signaling through the P2Y11R. On maturation, MoDCs down-regulated P2Y11R expression and were less sensitive to ATP-mediated inhibition of migration. In contrast, ATP did not inhibit the migration of CD1c+ peripheral blood (PB) DCs or interleukin-3 receptor-positive (IL-3R+) plasmacytoid DCs. Although all 4 DC populations expressed mRNA for P2Y11R, calcium-flux studies showed that blood DC types were unresponsive to P2Y11R agonists. In conclusion, DCs use distinct subtypes of P2R. The formation of ATP gradients at sites of inflammation may transiently inhibit the migration of local DCs, thus prolonging the time of antigen encounter. P2R inhibition may represent a new strategy to improve the migration of antigen-loaded DCs from the vaccination site to lymph nodes.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin, Australia. max.schnurr@ludwig.edu.au
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Tracey
authors.initials: T
authors.lastname: Toy
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stoitzner
authors.forename: Paul
authors.initials: P
authors.lastname: Cameron
authors.forename: Amanda
authors.initials: A
authors.lastname: Shin
authors.forename: Tina
authors.initials: T
authors.lastname: Beecroft
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D018949:Antigens, CD1 / Q000032:analysis; D020013:Calcium Signaling / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D003713:Dendritic Cells / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D003864:Depression, Chemical; D020405:Dermis / Q000166:cytology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007249:Inflammation; D016898:Interferon-alpha / Q000494:pharmacology; D008545:Melanoma / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D008565:Membrane Proteins / Q000494:pharmacology / Q000627:therapeutic use; D009000:Monocytes / Q000166:cytology; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016185:Receptors, Interleukin-3 / Q000032:analysis; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D010738:Type C Phospholipases / Q000502:physiology
chemical_list: D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; D016898:Interferon-alpha; D008565:Membrane Proteins; C109734:P2RY11 protein, human; D012333:RNA, Messenger; D016185:Receptors, Interleukin-3; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; C084881:flt3 ligand protein; D000255:Adenosine Triphosphate; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D015232:Dinoprostone