title: 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 E(2) (PGE(2)) signaling has been shown to be pivotal for DC migration toward lymph node-derived chemokines in vitro and in vivo. Here, we demonstrate that PGE(2) induced the expression of the costimulatory molecules OX40L, CD70, and 4-1BBL on human DCs. Short triggering by PGE(2) 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 PGE(2) on both monocyte-derived (Mo) DCs and peripheral blood myeloid (PB) DCs. PGE(2)-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 PGE(2)-matured MoDCs. Moreover, MoDCs matured in the presence of PGE(2) 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.
authors.affiliation: Biotechnology Institute Thurgau (BITg), University of Konstanz, Kreuzlingen, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Krause
authors.forename: Markus
authors.initials: M
authors.lastname: Bruckner
authors.forename: Christina
authors.initials: C
authors.lastname: Uermösi
authors.forename: Eva
authors.initials: E
authors.lastname: Singer
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Legler
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism; D053282:CD27 Ligand / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D053278:OX40 Ligand / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D053330:4-1BB Ligand; D000943:Antigens, Differentiation; D053282:CD27 Ligand; D053278:OX40 Ligand; C406562:OX40Ig; D015232:Dinoprostone