Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2 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 migratoryand 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-␥ 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

Prostaglandin E2 modulates the functional responsiveness of human monocytes to chemokines

“…Our data are in agreement with recent findings that showed an enhanced response of dendritic cells to the chemokines SLC and ELC in the presence of PGE 2 without a concomitant enhancement of the expression of the specific chemokine receptor CCR7 [14,15]. In addition, a study by Kurth et al [23] Of note, our data show that PGE 2 exerts its effects on human monocytes independently of chemokine receptor expression.…”

“…They are members of the family of G protein-coupled receptors and appear to be differentially expressed among inflammatory cells. Recent studies indicate that PGE 2 can modulate the migratory capacity of different cell types, such as endothelial [10,11], mesangial [12], and tumor cells [13] as well as dendritic cells [14,15].…”

Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model

“…Upon maturation, CCR7 expression was induced on MUTZ-3 IDC and MUTZ-3 LC, and this expression was accompanied by responsiveness to LNhoming chemokines CCL19 and CCL21. Interestingly, and unlike migration of MoDC (30,31), migration of MUTZ-3 IDC and MUTZ-3 LC was independent (IDC) or less dependent (LC) on PGE 2 . Importantly, so far it is not clear whether CD34-derived IDC or LC migration is dependent on PGE 2 .…”

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

“…Similar to the effect of PGI 2 analogs, PGE 2 has been shown to inhibit IL-12, TNF-␣, and IL-6 production by BMDCs, suppress MHC class II expression, and enhance IL-10 production (22,29,38,39). Studies showed that DCs may be activated to produce high levels of proinflammatory cytokines and remain at sites of inflammation or develop into CCR7-expressing cells that allow them to migrate to the draining lymph nodes and induce Ag-specific immune responses (50,51). These migratory DCs produce low levels of inflammatory cytokines (50).…”