Prostaglandin D₂ affects the differentiation and functions of human dendritic cells: impact on the T cell response

Abstract

The local environment in which dendritic cells (DC) differentiate is important for the acquisition of their immunostimulatory properties. Since prostaglandin D 2 (PGD 2 ), a major prostanoid produced during inflammatory reactions, is involved in the control of immune responses, its effect on the differentiation and functions of human monocytederived dendritic cells (MDDC) was studied. We show that DC differentiated in the presence of PGD 2 (PG/DC) have an unusual phenotype, with modifications in the expression of molecules involved in antigen (Ag) capture and presentation, leading to higher endocytic and Ag-processing activities. However, under conditions that necessitated Ag processing and presentation, PG/DC have an impaired ability to stimulate naive T cells, whereas superAg-pulsed DC efficiently promote their proliferation. Upon lipopolysaccharide or TNF-a/IL-1b stimulation, PG/DC phenotypically mature but produce abnormal amounts of immunoregulatory cytokines (decreased IL-12p70/IL-10 ratio). Moreover, mature PG/DC fail to up-regulate the chemokine receptor CCR7 and show an impaired migration towards its ligand CCL19. Finally, PG/DC favor the differentiation of naive T cells toward Th2 cells, an effect dependent on IL-10 and inducible costimulator ligand expression by DC. Most of the herein described effects of PGD 2 on MDDC can be reproduced, usually with a higher efficacy, with a selective D prostanoid receptor (DP)1, but not DP2, agonist. Taken as a whole, these results demonstrate that PGD 2 impacts DC differentiation and functions, and extend the concept that it exerts important roles in immunity.

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…PGD 2 also affects human dendritic cell differentiation and modulates the pattern of immunoregulatory cytokine production, favoring naive T cells toward a Th2 phenotype (Gosset et al, 2005). PGD 2 may contribute to the control of allergic reactions and tumor formation (Gosset et al, 2005;Torres et al, 2008).…”

Cyclooxygenase-2 Deficiency in Macrophages Leads to Defective p110γ PI3K Signaling and Impairs Cell Adhesion and Migration

“…PGE 2 , PGF 2a , and PGD 2 were reported to modulate cell migration of neutrophils, monocytes, DCs, and T cells. PGD 2 is a chemotactic agent for DCs and Th2 cells, whereas PGF 2a was shown to induce neutrophil migration (23,24). PGE 2 enhances hematopoietic cell homing and modulates monocyte response to chemokines (25,26).…”

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

“…Activation of the DP 1 receptor by PGD 2 has been shown to produce vasodilation 10 and bronchodilation. 11 Furthermore, the DP 1 receptor is expressed by certain leukocyte populations, 12,13 including dendritic cells, where it controls various functions, including cytokine production. CRTH2 was originally identified as an orphan receptor expressed by Th2 lymphocytes.…”