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Published online before print August 14, 2007

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(Journal of Leukocyte Biology. 2007;82:1106-1114.)
© 2007 by Society for Leukocyte Biology

Prostaglandin E₂ is a key factor for monocyte-derived dendritic cell maturation: enhanced T cell stimulatory capacity despite IDO

Petra Krause^*, Eva Singer, Paula I. Darley, Janosch Klebensberger, Marcus Groettrup^*, and Daniel F. Legler^*,1

^* Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland;
Klinikum Konstanz, Konstanz, Germany; and Divisions of
Microbial Ecology and
Immunology, Department of Biology, University of Konstanz, Konstanz, Germany

¹ Correspondence: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland. E-mail: daniel.legler{at}bitg.ch

The exclusive ability of dendritic cells (DCs) to stimulate primary and secondary immune responses favors the use of antigen-loaded human monocyte-derived DCs (MoDCs) in vaccinations against tumors. Previous studies demonstrated that PGE₂ is fundamental during MoDC maturation to facilitate migration toward lymph node-derived chemokines. A recent study challenged the use of PGE₂, as PGE₂ induced IDO in mature MoDCs. In MoDCs compatible for clinical use, we now demonstrate that PGE₂ is responsible for IDO induction if matured by soluble CD40 ligand, LPS, or cytokines. In contrast, IDO expression in MoDCs matured by TLR3 triggering occurs independently of PGE₂. It is surprising that despite active IDO protein, MoDCs matured with PGE₂ display a greater potential to stimulate naïve CD4⁺ and CD8⁺ T cell proliferation, which is not increased further by IDO inhibition. Moreover, we found elevated levels of tryptophanyl-tRNA-synthetase (TTS) in T cells cultured with PGE₂-matured MoDCs. Our data demonstrate that PGE₂ induces IDO in MoDCs but that T cell-stimulating capacities of PGE₂-matured MoDCs overcome IDO activity, probably through TTS induction. As PGE₂ is critical for DC migration and enhances the capability of MoDCs to induce T cell proliferation, we highly recommend supplementing DC maturation stimuli with PGE₂ for use in clinical trials.

Key Words: cell proliferation • chemotaxis • vaccination