Plasticity of dendritic cell function in response to prostaglandin E2 (PGE2) and interferon-gamma (IFN-gamma)

Abstract

Current evidence suggests that maturing dendritic cells (DCs) acquire a migratory phenotype to induce T cell responses in lymph nodes or a proinflammatory phenotype to condition the microenvironment at peripheral sites. We show that the interplay of PGE(2) and IFN-gamma generates a more complex pattern of mixed DC phenotypes in response to TLR stimulation. DCs activated by the TLR ligand R-848 in the presence of IFN-gamma and PGE(2) produced high levels of IL-12p70 and IL-23, started migration toward CCL19 within only 10 h, and still continued to secrete IL-12p70 without further restimulation following the migration step. The accelerated onset of migration was a result of PGE(2) and was associated with reduced plastic adherence and lower amounts of activated CD29. In contrast, IFN-gamma by itself enhanced cell adhesion and strongly hindered CCR7-mediated migration in the absence of PGE(2). This suggests a new role for IFN-gamma in the direct regulation of DC migration through enhanced cell adhesion, perhaps to support the development of T cell effector functions at peripheral sites. Together, our data are relevant to the development of DC vaccines, as they demonstrate the existence of dual-functional DCs, which as a result of the simultaneous effects of PGE(2) and IFN-gamma, can migrate rapidly toward lymph node chemokines and carry with them a wave of primary cytokines.