Human type 1 and type 2 conventional dendritic cells express indoleamine 2,3-dioxygenase 1 with functional effects on T cell priming

Simone P. Sittig, Jasper J.P. van Beek, Georgina Flórez-Grau, Jorieke Weiden, Sonja I. Buschow, Mirjam C. van der Net, Rianne van Slooten, Marcel M. Verbeek, P. Ben H. Geurtz, Johannes Textor, Carl G. Figdor, I. Jolanda M. de Vries*, Gerty Schreibelt

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
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Abstract

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3-dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN-γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR-stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC-T cell cell-cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross-present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC-based cancer vaccines with IDO inhibition.

Original languageEnglish
Pages (from-to)1494-1504
Number of pages11
JournalEuropean Journal of Immunology
Volume51
Issue number6
Early online date6 Mar 2021
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
This work was supported by a Radboudumc Ph.D. grant and Vici grant 918.14.655 from the Netherlands Organization for Scientific Research (NWO). C.G.F. is recipient of the NWO Spinoza Award and ERC Adv Grant ARTimmune (834618). J.T. is recipient of Dutch Cancer Society grant 10620. We thank Rob Woestenenk (cell sorting facility) for technical support.

Publisher Copyright:
© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH

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