Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells

Abstract

Dendritic cell (DC) based immunotherapy of malignant diseases relies on 2 critical parameters: antigen transport from the periphery to draining lymph nodes and efficient priming of primary and stimulation of secondary immune responses. Prostaglandin E2 (PGE2) signaling has been shown to be pivotal for DC migration toward lymph node derived chemokines in vitro and in vivo. Here, we demonstrate that PGE2 induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human DCs. Short triggering by PGE2 early during DC maturation was sufficient to induce the costimulatory molecules. The expression of the costimulatory molecules was independent of the maturation stimulus but strictly dependent on PGE2 on both monocyte-derived (Mo) DCs and peripheral blood myeloid (PB) DCs. PGE2-matured MoDCs showed enhanced costimulatory capacities resulting in augmented antigen-specific CD4+ and CD8+ T-cell proliferation in primary and recall T-cell responses. Blocking OX40/OX40L signaling impaired the enhanced T-cell proliferation induced by PGE2-matured MoDCs. Moreover, MoDCs matured in the presence of PGE2 induced the expression of OX40, OX40L, and CD70 on T cells facilitating T-cell/T-cell interaction that warrant long-lasting costimulation. This newly identified parameter will help to further optimize DC-based immunotherapy.