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Title: Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets.
Austin Authors: Luft, Thomas;Jefford, Michael;Luetjens, Petra;Toy, Tracey;Hochrein, Hubertus;Masterman, Kelly-Anne;Maliszewski, Charlie;Shortman, Ken;Cebon, Jonathan S ;Maraskovsky, Eugene
Affiliation: The Melbourne Tumour Biology Branch, The Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia
Issue Date: 15-Aug-2002
Publication information: Blood; 100(4): 1362-72
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.
Gov't Doc #: 12149219
DOI: 10.1182/blood-2001-12-0360
Journal: Blood
Type: Journal Article
Subjects: CD40 Ligand.physiology
Cell Differentiation
Cell Movement.drug effects
Cells, Cultured
Cyclic AMP.metabolism
Dendritic Cells.drug effects.physiology
Escherichia coli
Leukocytes, Mononuclear.drug effects.physiology
Lymphocyte Activation
Monocytes.drug effects.physiology
Receptors, CCR7
Receptors, CXCR4.analysis
Receptors, Chemokine.analysis
Receptors, Prostaglandin E.physiology
Receptors, Prostaglandin E, EP2 Subtype
Receptors, Prostaglandin E, EP4 Subtype
Signal Transduction
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