PMID- 33675038 OWN - NLM STAT- MEDLINE DCOM- 20210924 LR - 20211108 IS - 1521-4141 (Electronic) IS - 0014-2980 (Print) IS - 0014-2980 (Linking) VI - 51 IP - 6 DP - 2021 Jun TI - Human type 1 and type 2 conventional dendritic cells express indoleamine 2,3-dioxygenase 1 with functional effects on T cell priming. PG - 1494-1504 LID - 10.1002/eji.202048580 [doi] AB - 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-gamma 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. CI - (c) 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH. FAU - Sittig, Simone P AU - Sittig SP AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - van Beek, Jasper J P AU - van Beek JJP AUID- ORCID: 0000-0001-5888-0125 AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Florez-Grau, Georgina AU - Florez-Grau G AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Weiden, Jorieke AU - Weiden J AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Buschow, Sonja I AU - Buschow SI AD - Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands. FAU - van der Net, Mirjam C AU - van der Net MC AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - van Slooten, Rianne AU - van Slooten R AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Verbeek, Marcel M AU - Verbeek MM AD - Department of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Geurtz, P Ben H AU - Geurtz PBH AD - Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Textor, Johannes AU - Textor J AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Figdor, Carl G AU - Figdor CG AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - de Vries, I Jolanda M AU - de Vries IJM AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. AD - Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Schreibelt, Gerty AU - Schreibelt G AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210322 PL - Germany TA - Eur J Immunol JT - European journal of immunology JID - 1273201 RN - 0 (Cancer Vaccines) RN - 0 (IDO1 protein, human) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - 0 (Oximes) RN - 0 (Sulfonamides) RN - 71596A9R13 (epacadostat) SB - IM MH - Cancer Vaccines MH - Cell Differentiation MH - Cell Proliferation MH - Cells, Cultured MH - Coculture Techniques MH - Cross-Priming MH - Dendritic Cells/*immunology MH - Gene Expression Regulation MH - Homeostasis MH - Humans MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors/genetics/*metabolism MH - Lymphocyte Activation MH - Molecular Targeted Therapy MH - Organ Specificity MH - Oximes/pharmacology MH - Phenotype MH - Sulfonamides/pharmacology MH - T-Lymphocytes/*immunology PMC - PMC8251546 OTO - NOTNLM OT - IDO OT - cDC1 OT - cDC2 OT - epacadostat OT - plasmacytoid dendritic cells COIS- The authors declare no commercial or financial conflict of interest. EDAT- 2021/03/07 06:00 MHDA- 2021/09/25 06:00 PMCR- 2021/07/02 CRDT- 2021/03/06 05:44 PHST- 2020/12/29 00:00 [revised] PHST- 2020/02/09 00:00 [received] PHST- 2021/03/02 00:00 [accepted] PHST- 2021/03/07 06:00 [pubmed] PHST- 2021/09/25 06:00 [medline] PHST- 2021/03/06 05:44 [entrez] PHST- 2021/07/02 00:00 [pmc-release] AID - EJI5013 [pii] AID - 10.1002/eji.202048580 [doi] PST - ppublish SO - Eur J Immunol. 2021 Jun;51(6):1494-1504. doi: 10.1002/eji.202048580. Epub 2021 Mar 22.