title: Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets.
abstract: Migration of antigen (Ag)-loaded dendritic cells (DCs) from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. We evaluated monocyte-derived DCs (MoDCs) and peripheral blood DCs (PBDCs) to respond to proinflammatory mediators, CD40L, and intact bacteria. All classes of stimuli induced DC phenotypic maturation. However, for MoDCs, only prostaglandin E(2) (PGE(2))-containing stimuli induced migratory-type DCs. Thus, immature MoDCs that encountered proinflammatory cytokines or CD40L or intact bacteria in the presence of PGE(2) acquired migratory capacity but secreted low levels of cytokines. Conversely, MoDCs that encountered pathogens or CD40L alone become nonmigratory cytokine-secreting cells (proinflammatory type). Interestingly, both migratory- and proinflammatory-type DCs expressed equivalent levels of chemokine receptors, suggesting that the role of PGE(2) was to switch on migratory function. We demonstrate that PGE(2) induces migration via the E-prostanoid 2/E-prostanoid 4 (EP(2)/EP(4)) receptors and the cAMP pathway. Finally, migratory-type MoDCs stimulated T-cell proliferation and predominantly IL-2 secretion, whereas proinflammatory-type MoDCs induced IFN-gamma production. In contrast, CD1b/c(+) PBDC rapidly acquired migratory capacity irrespective of the class of stimulus encountered and secreted low levels of cytokines. This suggests that not all mature stages of DCs are destined to migrate to lymphoid organs and that the sequence in which stimuli are encountered significantly affects which functions are expressed. Thus, certain immature DC subsets recruited from the resting precursor pool may have multiple functional fates that play distinct roles during the induction and effector phases of the immune response. These findings have important implications for the clinical utility of DCs in immunotherapy.
authors.affiliation: The Melbourne Tumour Biology Branch, The Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
authors.forename: Michael
authors.initials: M
authors.lastname: Jefford
authors.forename: Petra
authors.initials: P
authors.lastname: Luetjens
authors.forename: Tracey
authors.initials: T
authors.lastname: Toy
authors.forename: Hubertus
authors.initials: H
authors.lastname: Hochrein
authors.forename: Kelly-Anne
authors.initials: KA
authors.lastname: Masterman
authors.forename: Charlie
authors.initials: C
authors.lastname: Maliszewski
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
mesh_terms: D023201:CD40 Ligand / Q000502:physiology; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology* / Q000502:physiology; D004926:Escherichia coli; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008213:Lymphocyte Activation; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000032:analysis; D019707:Receptors, Chemokine / Q000032:analysis; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C515370:CCR7 protein, human; D016207:Cytokines; D007376:Interleukin-2; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D023201:CD40 Ligand; D007371:Interferon-gamma; D000242:Cyclic AMP; D015232:Dinoprostone